Complications of HIV Infection: A Systems-Based Approach

CAROLYN CHU; PETER A. SELWYN

CAROLYN CHU, MD, MSc, AND PETER A. SELWYN, MD, MPH

Am Fam Physician. 2011;83(4):395-406

A more recent article on HIV-associated complications is available.

See related editorial on page 375.

Author disclosure: Nothing to disclose.

Patients with human immunodeficiency virus (HIV) infection often develop multiple complications and comorbidities. Opportunistic infections should always be considered in the evaluation of symptomatic patients with advanced HIV/AIDS, although the overall incidence of these infections has decreased. Primary care of HIV infection includes the early detection of some complications through screening at-risk and symptomatic patients with routine laboratory monitoring (e.g., comprehensive metabolic and lipid panels) and validated tools (e.g., the HIV Dementia Scale). Treatment of many chronic complications is similar for patients with HIV infection and those without infection; however, combination antiretroviral therapy has shown benefit for some conditions, such as HIV-associated nephropathy. For other complications, such as cardiovascular disease and lipoatrophy, management may include switching antiretroviral regimens to reduce exposure to HIV medications known to cause toxicity.

As the prevalence of human immunodeficiency virus (HIV) and AIDS increases, and as survival rates improve with combination antiretroviral therapy, more primary care physicians are treating patients with HIV infection. Additionally, more than 20 percent of patients with HIV infection remain undiagnosed, and may initially present with AIDS-defining illnesses.¹ Although the overall incidence of many opportunistic infections has decreased with effective chemoprophylaxis and combination antiretroviral therapy,² prompt recognition and appropriate management are imperative to decrease mortality related to these conditions. Primary care management of HIV infection includes preventing and treating opportunistic infections, monitoring antiretroviral therapy, and treating chronic HIV-related complications.

Clinical recommendation	Evidence rating	References
Patients with HIV infection who have new cognitive, behavioral, or motor abnormalities should be screened for HIV-associated neurocognitive disorders.	C	¹², ¹³
Management of cardiovascular risk and dyslipidemia in patients with HIV infection should be based on guidelines from the National Cholesterol Education Program, Adult Treatment Panel III.	C	²⁴
At the time of HIV diagnosis, patients should be screened for kidney disease, and a calculated estimate of renal function should be made. Patients at high risk of kidney disease should undergo annual screening.	C	⁵⁴
Baseline screening for glucose and lipid disorders should be performed for all patients with HIV infection at the time of diagnosis, with fasting blood glucose levels and lipid profiles monitored routinely thereafter (i.e., every six to 12 months).	C	²⁴, ⁴²
Patients should be evaluated for potential drug interactions between antiretrovirals (particularly protease inhibitors) and commonly prescribed medications (e.g., statins, calcium channel blockers, antiepileptics). Interactions may lead to complications such as myopathy, rhabdomyolysis, and possibly HIV treatment failure.	C	⁶⁶

Some complications of HIV infection are the direct result of long-term infection, whereas others are the indirect result of aging, antiretroviral therapy, or other patient factors. Physicians should always consider the patient's most recent CD4 lymphocyte count (and nadir, if known) and assess preexisting conditions, medication use, health behaviors, and recent exposures. Although many opportunistic infections (e.g., pneumocystosis, toxoplasmosis, cryptococcosis) occur in patients with low CD4 lymphocyte counts, others (e.g., oral candidiasis, tuberculosis) can appear at any level.

This article reviews key complications in patients who have HIV infection, with an emphasis on neurologic, cardiopulmonary, and gastrointestinal disorders (Table 1). Important antiretroviral-associated complications are included because of their relevance to primary care physicians. Previously published articles provide additional information.^3–5 Online resources also provide detailed information on the diagnosis and management of opportunistic infections (Table 2).

System	Direct effect of HIV infection	Common complications	Associated pathogens	Antiretroviral treatment- related adverse effects
Neuropsychiatric (Table 3)	HIV-associated neurocognitive disorders, neuropathy, radiculopathy, myelopathy	Primary central nervous system lymphoma	Cryptococcus neoformans, CMV, JC virus, Toxoplasma gondii	Efavirenz (Sustiva): vivid dreams, sedation NRTIs: peripheral neuropathy
Neuropsychiatric (Table 3)		Chronic psychiatric disorders	Cryptococcus neoformans, CMV, JC virus, Toxoplasma gondii
Head and neck	HIV-associated retinopathy	Gingivitis, dental and salivary gland disease	—
Head and neck	HIV-associated retinopathy	Gingivitis, dental and salivary gland disease	—	Retinitis: CMV, T. gondii Acute retinal necrosis and progressive outer retinal necrosis: HSV, varicella zoster virus Otitis, sinusitis: invasive fungi
Cardiovascular	HIV-associated cardiomyopathy	Cardiovascular disease, endocarditis	Myocarditis, pericarditis: CMV, invasive fungi, Mycobacterium species, T. gondii	Abacavir (Ziagen): cardiotoxicity* Protease inhibitors: dyslipidemia
Cardiovascular	Atherosclerosis	Cardiovascular disease, endocarditis
Pulmonary	HIV-associated pulmonary hypertension	Chronic obstructive pulmonary disease, lung cancer (including Kaposi sarcoma and lymphoma)	Pneumonia, pneumonitis: CMV, invasive fungi, Pneumocystis jiroveci (formerly Pneumocystis carinii), T. gondii Pulmonary tuberculosis: Mycobacterium tuberculosis	—
Pulmonary	Emphysema*			—
Gastrointestinal (Table 4)	HIV-induced enteropathy	Viral hepatitis, lymphoma, Kaposi sarcoma, HPV- related malignancies	Candida species, CMV, HSV, protozoa	NRTIs: pancreatitis Protease inhibitors: diarrhea, fatty liver*
Gastrointestinal (Table 4)	Nonalcoholic fatty liver disease*		Candida species, CMV, HSV, protozoa
Renal/genitourinary	HIV-associated nephropathy	Chronic kidney disease not caused by HIV- associated nephropathy	Sexually transmitted infections (e.g., Chlamydia trachomatis)	Protease inhibitors: nephrolithiasis Tenofovir (Viread): nephrotoxicity
Endocrine	Impaired lipid and glucose metabolism	—	Adrenal gland infiltration: CMV, invasive fungi, Mycobacterium species	Protease inhibitors: lipid or glucose disorders, lipodystrophy
	HIV-associated wasting
	Lipodystrophy
	Hypogonadism,* premature ovarian failure
Musculoskeletal	Myopathy, myositis	Osteopenia, osteoporosis, osteonecrosis	—	NRTI or NNRTIs: osteomalacia* Protease inhibitors with statins: myopathy
Hematologic or oncologic	Anemia of chronic disease	Lymphoma, multiple myeloma	Bone marrow infiltration (leading to pancytopenia): CMV, invasive fungi, Mycobacterium species	Zidovudine (Retrovir) and trimethoprim/sulfamethoxazole (Bactrim, Septra): anemia
Hematologic or oncologic	Coagulation disorders*	Lymphoma, multiple myeloma
Dermatologic	Eosinophilic folliculitis*	Papulosquamous disorders (e.g., eczema, seborrheic dermatitis, psoriasis); molluscum contagiosum; Kaposi sarcoma	Fungal dermatoses, varicella zoster virus	—

Many HIV-associated complications, such as dyslipidemia, are familiar to primary care physicians. Managing these complications is often possible without extensive input from an HIV expert, although special attention should be given to patients taking antiretroviral drugs because of polypharmacy. Primary care physicians should also include preventive care, health promotion (e.g., safe sex education), and psychosocial assessments as part of routine care for all patients with HIV infection.

Neuropsychiatric System

CENTRAL NERVOUS SYSTEM COMPLICATIONS

Advanced HIV infection can lead to opportunistic infections of the brain and spinal cord (Table 3⁶ ). Well-known pathogens include Toxoplasma gondii (Figure 1), Cryptococcus neoformans, and JC virus. Primary central nervous system lymphoma may also affect severely immunocompromised patients (Figure 2). Infections and malignancy cause variable neurologic symptoms, usually reflecting the location and severity of disease. For example, patients with solitary lesions often present with headache or focal deficits, whereas patients with increased intracranial pressure from substantial masses (with or without edema) may have visual disturbances, nausea, or altered consciousness. Patients with meningitis or encephalitis generally present with one or more of the following: fever, headache, neck pain or stiffness, altered mental status, or seizure. Symptoms of myelopathy include weakness and sensory changes; upper motor neuron signs, such as spasticity and hyperreflexia, may also be found.

Complication*		Signs and symptoms	Typical CD4 lymphocyte count	Diagnostic evaluation
Complication*		Signs and symptoms	Typical CD4 lymphocyte count	Imaging	Serology	Microbiology/other
Cerebral toxoplasmosis		Focal neurologic deficits, confusion, occasional fever or headache; seizure or coma with progressive disease	< 50 per mm³ (0.05 × 10⁹ per L)	Contrast MRI or CT usually shows one or more ring-enhancing lesions with edema, with or without mass effect	Serum toxoplasma immunoglobulin G is often positive (absence makes diagnosis less likely)	Brain biopsy is recommended if patients do not improve with empiric therapy
Cerebral toxoplasmosis			< 50 per mm³ (0.05 × 10⁹ per L)			CSF analysis is rarely performed
Cryptococcal meningoencephalitis (or cryptococcoma)		Headache, fever, confusion, altered mental status	< 50 per mm³	—	Serum cryptococcal antigen is almost always positive	Fungal cultures and CSF or blood staining may yield organism
Cryptococcal meningoencephalitis (or cryptococcoma)		Headache, fever, confusion, altered mental status	< 50 per mm³	—	CSF antigen may be elevated
Viral meningoencephalitis		In general: fever, headache, confusion, delirium, lethargy, focal deficits, occasionally seizure (virus-specific symptoms listed below)	—	—	—	PCR of CSF (or brain tissue), special staining, viral culture
	Cytomegalovirus	Worsening focal deficits	< 50 per mm³	Periventricular enhancement on MRI
	Herpes simplex virus	Behavioral, personality, or memory changes	< 200 per mm³ (0.20 × 10⁹ per L)	Diffuse edema, occasionally shows necrosis of frontal and temporal lobes (MRI more sensitive than CT)
	Herpes simplex virus	Behavioral, personality, or memory changes	< 200 per mm³ (0.20 × 10⁹ per L)	Electroencephalography often shows characteristic focal temporal abnormalities
	Varicella zoster virus	Vasculitis, leading to stroke syndromes	Risk increases with lower CD4 count	Diffuse edema with demyelination, possible focal infarcts (MRI more sensitive than CT)
Progressive multifocal leukoencephalopathy		Progressive focal deficits (e.g., cognitive decline, cranial nerve palsy, aphasia, ataxia, weakness or sensory loss, seizure); may progress to coma	< 200 per mm³	Single or multiple white matter lesions with little to no enhancement and no edema or mass effect (MRI more sensitive than CT)	—	Brain biopsy is definitive but rarely performed
Progressive multifocal leukoencephalopathy			< 200 per mm³		—	PCR detection of JC virus in CSF helps confirm diagnosis
Neurosyphilis		Wide range of symptoms (e.g., behavioral and psychological abnormalities, delirium, dementia, focal deficits, stroke syndromes related to arteritis, ocular and auditory changes, meningitis, myelitis)	< 350 per mm³ (0.35 × 10⁹ per L)	—	CSF VDRL test is specific but not sensitive; reactive test confirms diagnosis (nonreactive test does not exclude diagnosis) CSF treponemal tests (e.g., FTA-ABS) are sensitive but not specific; nonreactive test excludes diagnosis†	CSF typically shows elevated protein level and mononuclear pleocytosis (white blood cell count > 10 to 20 per μL [.01 to .02 × 10⁹ per L])
Neurosyphilis		Risk increases when serum rapid plasma reagin titer ≥ 1:32	< 350 per mm³ (0.35 × 10⁹ per L)	—
Primary central nervous system lymphoma		Focal neurologic deficits, headache, blurred vision, seizure, motor difficulty, personality or cognitive changes, confusion	Risk increases with lower CD4 count	Solitary white matter lesions on CT or MRI, often with mild edema and mass effect	—	Brain biopsy is definitive, although CSF examination for cytology, flow cytometry, and PCR testing may also be useful
				Multicentric lymphoma occurs less frequently
				PET/SPECT is occasionally useful to differentiate from cerebral toxoplasmosis

Research describes a spectrum of deficits (wider than previously thought) that arise from HIV-mediated neurotoxicity and inflammation, especially in patients with a history of low CD4 lymphocyte counts.^7–9 Impairment ranges from mild (asymptomatic neurocognitive impairment) to severe (HIV-associated dementia). Collectively, these are termed HIV-associated neurocognitive disorders. HIV-associated dementia is an AIDS-defining condition involving deficits in at least two cognitive ability domains (e.g., memory, attention and concentration) and abnormalities in motor or neurobehavioral function that impair activities of daily living. Brief screening instruments are available, such as the HIV Dementia Scale (Figure 3^10,11 ),¹² although extensive neuropsychological testing may be needed in some cases. Data are limited regarding treatment of HIV-associated neurocognitive disorders. Researchers are investigating whether antiretroviral drugs with sufficient central nervous system penetration can significantly improve symptoms or prevent further cognitive decline. Antibacterials, antiinflammatories, and antioxidants have not shown benefit.

Evidence suggests that neurodegenerative disorders, such as early-onset Alzheimer disease, are increasing disproportionately in patients with HIV infection, even in those with well-controlled HIV disease.^13,14 This, in addition to the potential impact of HIV-associated neurocognitive disorders, has fueled concerns that the aging population with HIV infection will be vulnerable to neurologic and functional decline and increasing frailty and disability.

OTHER NEUROPSYCHIATRIC COMPLICATIONS

HIV usually affects the peripheral neurologic system as neuropathy (i.e., distal sensory polyneuropathy) or radiculopathy (usually a lumbrosacral polyradiculopathy).¹⁵ These conditions may be exacerbated by antiretroviral drug use or other conditions (e.g., diabetes mellitus). Polyradiculopathy may also be caused by cytomegalovirus in patients with AIDS. Patients with distal sensory polyneuropathy generally present with symptoms of paresthesia, dysesthesia, or numbness of the bilateral extremities, whereas patients with lumbosacral radiculopathy typically experience radiating back pain, occasional asymmetric leg weakness, sacral or lower extremity sensory loss, and possible bowel or bladder dysfunction. Examination findings include decreased or absent deep tendon reflexes and impaired vibration/pinprick perception. In addition to a thorough neurologic examination, the diagnosis of peripheral neurologic system complications may require electromyography, nerve conduction studies, or magnetic resonance imaging of the brain or spinal cord to evaluate for central lesions and peripheral nerve root impingement. Occasionally, cerebrospinal fluid examination may be warranted to look for opportunistic pathogens.

Studies estimate that up to 50 percent of patients with HIV infection have concurrent chronic psychiatric and substance use disorders.¹⁶ Such conditions are not directly related to infection, but occasionally decrease quality of life and interfere with treatment adherence. Therefore, many HIV clinics routinely screen for these conditions at the initial visit and at regular intervals thereafter.

Cardiopulmonary System

CARDIOVASCULAR COMPLICATIONS

Studies demonstrate higher rates of myocardial infarction and atherosclerosis in patients with HIV infection.^17,18 HIV appears to independently increase the risk of cardiovascular disease via elevated cytokine levels, chronic vascular inflammation, and endothelial dysfunction.¹⁹ Traditional risk factors, such as smoking, are also prevalent in patients with HIV infection.²⁰ Virally mediated vascular effects may then be compounded by lipid or metabolic changes caused by infection and antiretroviral use. For example, abacavir (Ziagen) has been widely investigated for direct cardiotoxicity.^21–23 Currently, cardiac risk assessment and dyslipidemia recommendations for persons with HIV infection are based on the National Cholesterol Education Program, Adult Treatment Panel III guidelines. In addition, some experts suggest that extra attention be paid to current and previous antiretroviral exposure (i.e., abacavir, protease inhibitors) when evaluating patients for cardiovascular disease.²⁴ Ongoing studies are assessing the benefits of switching antiretroviral drugs²⁵; however, the possibilities of new toxicities and virologic rebound must be weighed against traditional options (i.e., lipidlowering therapy).

Other HIV-associated cardiac complications (i.e., cardiomyopathy, myocarditis, and pericarditis) are still reported, although their incidence has decreased as combination antiretroviral therapy has become widespread.²⁶ This decrease may be partly attributable to a reduction in opportunistic infections. Infective endocarditis occurs almost exclusively in those who use injection drugs.

PULMONARY COMPLICATIONS

Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia remains relatively common in patients with HIV infection, and may be the presenting manifestation of HIV in patients who have not yet been diagnosed.²⁷ Patients with P. jiroveci pneumonia classically present with fever, progressive exertional dyspnea, and nonproductive cough. Although there are a wide variety of radiologic findings, chest radiography typically shows bilateral interstitial infiltrates (Figure 4). Empiric treatment is appropriate in patients with mild, classic symptoms and CD4 lymphocyte counts of 200 per mm³ (0.20 × 10⁹ per L) or less. However, further diagnostic techniques (e.g., induced sputum examination, transbronchial biopsy with or without bronchoalveolar lavage) should be used if patients do not improve after four to five days of empiric therapy.^28,29 Severe pneumococcal pneumonia and infections caused by atypical organisms (i.e., Legionella species) or other opportunistic pathogens should also be considered, depending on CD4 lymphocyte counts and geographic location.

Rates of pulmonary arterial hypertension, chronic obstructive pulmonary disease, and lung cancer have remained the same or increased in patients with HIV infection over the past few decades.^30–33 Although the exact etiology of HIV-associated pulmonary hypertension is largely unknown, vascular pathologic changes and clinical presentation (e.g., exertional dyspnea, fatigue, cough, edema) are similar to those in patients without HIV infection. Initial evaluation involves electrocardiography and echocardiography. Imaging and pulmonary function tests can help exclude other diagnoses. Cardiac catheterization is considered the diagnostic standard to quantify pulmonary pressure and guide treatment, which may include diuretics, digoxin, calcium channel blockers, anticoagulants, and supplemental oxygen. Agents targeting the prostacyclin, nitric oxide, and endothelin pathways (i.e., epoprostenol (Flolan), sildenafil (Revatio), and bosentan (Tracleer) are also used. The effect of combination antiretroviral therapy on the clinical course and prognosis of HIV-associated pulmonary hypertension remains uncertain.

Additionally, research suggests that HIV accelerates emphysema-associated processes in patients who smoke, leading to earlier development and high rates of chronic obstructive pulmonary disease.³² HIV also appears to raise the risk of lung cancer, even independent of smoking (one study reported a hazard ratio of 3.6).³³ Because studies have yet to determine whether antiretroviral therapy alters chronic obstructive pulmonary disease and lung cancer development in patients with HIV infection, tobacco cessation remains the most important preventive measure for those with HIV who smoke.

Gastrointestinal and Hepatic Systems

ORAL AND ESOPHAGEAL DISEASE

HIV-related upper digestive tract complications are well documented.³⁴ Candidal infection often affects the oral cavity, leading to dysphagia or odynophagia (Figure 5), or the esophagus, manifesting as sharp or burning substernal discomfort. Aphthous ulcers and oral ulcers/esophagitis caused by cytomegalovirus or herpes simplex virus (Figure 6) may also occur, especially in patients with CD4 lymphocyte counts of 200 per mm³ or less. Diagnosis of these viral infections is made by histologic examination after biopsy; aphthous ulcers should be considered in patients with oral/esophageal ulcers only after excluding infections. Physicians should also routinely examine patients for oropharyngeal cancer, given the prevalence of oral human papillomavirus (11 to 37 percent), smoking, and alcohol use in patients with HIV infection.^35,36

OTHER DIGESTIVE TRACT COMPLICATIONS

The assessment of gastrointestinal complications is often directed by the degree of immunosuppression and the nature and duration of symptoms (Table 4⁶ ). Diarrhea is a common symptom in adults with HIV infection. In one sample, approximately 40 percent of patients reported at least one episode of diarrhea in the preceding month.³⁷ HIV also directly invades various intestinal cell populations and disturbs gut motility by affecting the autonomic nervous system, leading to HIVassociated enteropathy.³⁸ Slightly higher rates of inflammatory bowel disease have been reported in patients with HIV infection,³⁹ although reasons for this are unclear.

Complication*	Signs and symptoms	Typical CD4 lymphocyte count	Diagnostic evaluation
Complication*	Signs and symptoms	Typical CD4 lymphocyte count	Microbiology/histology	Other
Cytomegalovirus infection	Fever, anorexia, abdominal pain or bloating, watery diarrhea (occasionally bloody); possible perforation	< 50 to 100 per mm³ (0.05 to 0.10 × 10⁹ per L)	Colonoscopy with biopsy to visualize mucosal erosion and ulcerations, and demonstrate intranuclear and intracytoplasmic viral inclusions	Mucosal tissue may be sent for cytomegalovirus antigen detection through immunostaining
Infection from Cryptosporidium species, microsporidia, or Isospora belli	Anorexia, nausea, vomiting, cramps, profuse watery (nonbloody) diarrhea; malabsorption is common	< 100 per mm³	Stool or biopsy tissue for microscopic identification and staining	Cryptosporidium oocysts can be detected by direct immunofluorescence or ELISA
		< 100 per mm³		Determination of microsporidia can be made with transmission electron microscopy, special antibody staining, or PCR
HIV-induced enteropathy (or AIDS enteropathy)	Chronic diarrhea, with occasional weight loss from malabsorption	More common in patients with advanced HIV disease (i.e., CD4 count < 200 per mm³ [0.20 × 10⁹ per L])	—	Diagnosis of exclusion
Intestinal malignancies (e.g., non-Hodgkin lymphoma, Kaposi sarcoma, anal squamous cell carcinoma)	Abdominal or rectal pain, nausea, vomiting, diarrhea, intestinal bleeding, malabsorption, weight loss if direct involvement	Tends to occur in patients with advanced HIV infection (i.e., CD4 count < 200 per mm³)	Endoscopy with biopsy	—
	Extraluminal tumors may cause symptoms through indirect involvement (e.g., leading to obstruction)		Endoscopy with biopsy	—
Fat malabsorption (pancreatic exocrine insufficiency)	Weight loss, abdominal bloating, steatorrhea, foul-smelling stools, flatulence	Can occur at any count	—	Quantitative: 72-hour stool fat analysis, fecal elastase
Fat malabsorption (pancreatic exocrine insufficiency)		Can occur at any count	—	Qualitative: Sudan black B fat staining
Proctitis and anorectal ulcers from sexually transmitted infections	Fecal urgency, crampy bowel movements, anorectal soreness, sensation of incomplete voiding, occasionally rectal bleeding or discharge	Can occur at any count	Swab (for Gram stain or culture) for sexually transmitted bacteria and viruses	Swab can also be obtained for PCR amplification
		Can occur at any count	Proctosigmoidoscopy with biopsy may be needed	Swab can also be obtained for PCR amplification
Protease inhibitor-related adverse effects	Nausea, abdominal discomfort or bloating, loose nonbloody stools	Can occur at any count	—	Consider diagnosis after other causes have been ruled out
Protease inhibitor-related adverse effects	Symptoms usually occur soon after medication initiation	Can occur at any count	—	Consider diagnosis after other causes have been ruled out

PANCREATIC AND HEPATOBILIARY COMPLICATIONS

HIV-associated pancreatitis is now primarily caused by antiretroviral use and hypertriglyceridemia, rather than opportunistic infections. Although acalculous cholecystitis may occur, the incidence of cholelithiasis does not appear to be increased by HIV.⁴⁰ Chronic liver disease from viral or nonviral hepatitis has become a leading cause of morbidity and mortality in patients with HIV infection; patients should be screened for viral hepatitis at the time of HIV diagnosis.^41–42 Nonalcoholic fatty liver disease has also been recognized as an important complication of HIV, especially in patients with hepatitis C coinfection. Nonalcoholic fatty liver disease is associated with various factors, including visceral adiposity, insulin resistance, dyslipidemia, and mitochondrial toxicity.^43,44 Because traditional inflammatory biomarkers are often normal and ultrasonography is somewhat insensitive, new biomarker panels and imaging modalities (i.e., transient elastography) are being investigated.⁴⁵ Treatment of nonalcoholic fatty liver disease currently focuses on reducing metabolic risk through lifestyle modifications (e.g., weight loss) and management of insulin resistance and hyperlipidemia. Hepatocellular carcinoma appears to affect persons who have HIV infection at younger ages compared with those who do not have HIV infection; therefore, surveillance sonography is recommended for at-risk persons, such as those with chronic hepatitis C or alcoholic cirrhosis.^46,47

Genitourinary System

GENITAL INFECTIONS

Because the individual and public health consequences of untreated sexually transmitted infections in patients with HIV infection are considerable, prompt diagnosis and management of these infections are essential. Genital herpes increases the risk of HIV transmission; studies have yet to confirm whether suppressive herpes treatment reduces this risk.^48,49 Management of most sexually transmitted infections in patients with HIV infection is similar to that for persons without HIV infection; however, higher doses of antivirals and a possibly longer duration of therapy are indicated for treating genital herpes in patients with HIV infection.⁵⁰ Additionally, elevated rates of high-risk human papillomavirus subtypes are found in patients with HIV infection, increasing their risk of anogenital tract dysplasia.³⁵

RENAL COMPLICATIONS

The spectrum of HIV-associated renal disease has evolved. Acute and subacute complications related to antiretroviral therapy, such as protease inhibitor–associated nephrolithiasis and nephrotoxicity from tenofovir (Viread) use, continue to occur. Rates of end-stage kidney disease caused by HIV-associated nephropathy have stabilized,⁵¹ whereas diabetes, hypertension, and hepatitis C are emerging as major risk factors for chronic kidney disease in patients with HIV infection.^52,53

At the time of HIV diagnosis, patients should be screened for kidney disease with urinalysis, and a calculated estimate of renal function with creatinine clearance or glomerular filtration rate should be made. HIVassociated nephropathy should be considered in patients with proteinuria and progressively worsening renal function; diagnosis requires kidney biopsy. Treatment consists of combination antiretroviral therapy and angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, and possibly steroids. In patients with undetectable HIV viral loads and CD4 lymphocyte counts greater than 200 cells per mm³, kidney transplantation may be considered. Annual testing for kidney disease is recommended for high-risk patients (e.g., blacks; patients with CD4 lymphocyte counts less than 200 per mm³ or HIV viral load greater than 4,000 RNA copies per mL; patients with comorbid diabetes, hypertension, or hepatitis C).⁵⁴

Metabolic and Endocrine Complications

INSULIN RESISTANCE, DIABETES, DYSLIPIDEMIA, AND LIPODYSTROPHY

Although abnormalities in glucose metabolism, lipid metabolism, and adipose tissue distribution are multifactorial, insulin resistance, diabetes, dyslipidemia, and lipodystrophy can occasionally be attributed to antiretroviral therapy.⁵⁵ These complications reflect complex interactions between the patient and traditional risk factors, medication effects, and infection (HIV causes chronic inflammation, immune system activation, etc.). Patients should be screened for glucose and lipid disorders at the time of diagnosis and routinely thereafter (i.e., every six to 12 months). Lipids should also be checked within three to six months of initiating new antiretroviral therapy.^24,42 Management of insulin resistance and diabetes in patients with HIV infection does not differ significantly from management in other patients; treatment is primarily based on guidelines from the American Diabetes Association.⁵⁶ If glucose-lowering medication is indicated, patients with HIV infection and diabetes who also have lipoatrophy may benefit from pioglitazone (Actos). Physicians may also consider switching antiretroviral medications to more glucose- or lipid-neutral regimens. Specific management of lipoatrophy includes thymidine analogue discontinuation, cosmetic procedures, or thiazolidinediones (statins are being investigated), whereas lipohypertrophy management includes lifestyle modifications, cosmetic procedures, and possibly metformin (Glucophage). Growth hormone–releasing factors are also being studied.

OTHER ENDOCRINE COMPLICATIONS

Disorders of the hypothalamic-pituitary-adrenal and gonadal axes have been reported in patients with HIV infection. In addition to peripheral causes, central nervous system lesions can involve the hypothalamus and pituitary gland, leading to adrenal insufficiency and hypogonadism. Adrenal insufficiency is usually mild and may also be caused by direct HIV infection of the adrenals, disseminated opportunistic infections, malignancy, or medication use (e.g., systemic ketoconazole [Nizoral]). Testosterone deficiency is common,⁵⁷ especially in men with advanced HIV infection or AIDS. Research also demonstrates that women with HIV infection commonly experience irregular menses and may be at higher risk of amenorrhea or premature ovarian failure.⁵⁸

Musculoskeletal System

Studies estimate a three- to sixfold increased risk of reduced bone mineral density in patients with HIV infection.⁵⁹ Preliminary work also suggests an increased prevalence of fractures.⁶⁰ Various antiretrovirals have been associated with osteopenia and osteoporosis, although other factors (e.g., weight, nadir CD4 lymphocyte count, menopausal status, chronic steroid use) may play a role.^61–64 Given the lack of data, osteoporosis screening for patients with HIV infection remains somewhat controversial. Some experts recommend screening at-risk patients (i.e., postmenopausal women, men older than 50 years) and treating based on risk calculation.⁶⁵ Patients with HIV infection are also vulnerable to osteomalacia and osteonecrosis, the latter involving ischemic subchondral bone tissue death. Osteonecrosis typically manifests as joint pain or stiffness, particularly in the groin, hips, or shoulders. Plain radiography (Figure 7) is an appropriate first step, although magnetic resonance imaging is more sensitive.

Myopathy from older nucleoside analogues may now be less common because of the availability of newer agents. HIV also causes an autoimmune-mediated myopathy. Physicians should be especially careful with patients on antiretrovirals (particularly protease inhibitors), because coadministration of these drugs with commonly prescribed medications (e.g., statins, calcium channel blockers, antiepileptics) may lead to myopathy, rhabdomyolysis, and possibly HIV treatment failure.⁶⁶

Centers for Disease Control and Prevention (CDC). HIV prevalence estimates— United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57(39):1073-1076.

Jones JL, Hanson DL, Dworkin MS, et al. Surveillance for AIDSdefining opportunistic illnesses, 1992–1997. MMWR CDC Surveill Summ. 1999;48(2):1-22.

Currier JS, Havlir DV. Complications of HIV disease and antiretroviral therapy. Top HIV Med. 2009;17(2):57-67.

Havlir DV, Currier JS. Complications of HIV disease and antiretroviral therapy. Top HIV Med. 2006;14(1):27-35.

Lesho EP, Gey DC. Managing issues related to antiretroviral therapy. Am Fam Physician. 2003;68(4):675-686.

Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.

González-Scarano F, Martín-García J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69-81.

Ellis R, Heaton R, Letendre S, et al. Higher CD4 nadir is associated with reduced rates of HIV-associated neurocognitive disorders in the CHARTER study: potential implications for early treatment initiation. Paper presented at: 17th Conference on Retroviruses and Opportunistic Infections; February 16–19, 2010; San Francisco, Calif.

Bhaskaran K, Mussini C, Antinori A, et al.; CASCADE Collaboration. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol. 2008;63(2):213-221.

Power C, Selnes OA, Grim JA, McArthur JC. HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol. 1995;8(3):273-278.

Davis HF, Skolasky RL, Selnes OA, Burgess DM, McArthur JC. Assessing HIV-associated dementia: modified HIV dementia scale versus the Grooved Pegboard. AIDS Read. 2002;12(1):29-31.

von Giesen HJ, Haslinger BA, Rohe S, Köller H, Arendt G. HIV Dementia Scale and psychomotor slowing—the best methods in screening for neuro-AIDS. J Neuropsychiatry Clin Neurosci. 2005;17(2):185-191.

Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL. Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS. 2005;19(4):407-411.

Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol. 2009;4(2):163-174.

Letendre SL, Ellis RJ, Everall I, Ances B, Bharti A, McCutchan JA. Neurologic complications of HIV disease and their treatment. Top HIV Med. 2009;17(2):46-56.

Bing EG, Burnam MA, Longshore D, et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry. 2001;58(8):721-728.

Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-2512.

Kingsley LA, Cuervo-Rojas J, Muñoz A, et al. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study. AIDS. 2008;22(13):1589-1599.

Ross AC, Rizk N, O'Riordan MA, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009;49(7):1119-1127.

Tesoriero JM, Gieryic SM, Carrascal A, Lavigne HE. Smoking among HIV positive New Yorkers: prevalence, frequency, and opportunities for cessation. AIDS Behav. 2010;14(4):824-835.

Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13(10):F63-F70.

Justman JE, Benning L, Danoff A, et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr. 2003;32(3):298-302.

Hsue PY, Hunt PW, Wu Y, et al. Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS. 2009;23(15):2021-2027.

Dubé MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37(5):613-627.

Eron JJ, Young B, Cooper DA, et al.; SWITCHMRK 1 and 2 investigators. Switch to a raltegravir-based regimen versus continuation of a lopinavirritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396-407.

Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000;40(3):282-284.

Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30(suppl 1):S5-S14.

Masur H, Shelhamer J. Empiric outpatient management of HIV-related pneumonia: economical or unwise?. Ann Intern Med. 1996;124(4):451-453.

Wilkin A, Feinberg J. Pneumocystis carinii pneumonia: a clinical review. Am Fam Physician. 1999;60(6):1699-1708.

Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177(1):108-113.

Spano JP, Massiani MA, Bentata M, et al. Lung cancer in patients with HIV infection and review of the literature. Med Oncol. 2004;21(2):109-115.

Diaz PT, King ER, Wewers MD, et al. HIV infection increases susceptibility to smoking-induced emphysema. Chest. 2000;117(5 suppl 1):285S.

Kirk GD, Merlo C, O'Driscoll P, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis. 2007;45(1):103-110.

Wilcox CM, Saag MS. Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut. 2008;57(6):861-870.

Cameron JE, Hagensee ME. Oral HPV complications in HIV-infected patients. Curr HIV/AIDS Rep. 2008;5(3):126-131.

Gillison ML. Oropharyngeal cancer: a potential consequence of concomitant HPV and HIV infection. Curr Opin Oncol. 2009;21(5):439-444.

Knox TA, Spiegelman D, Skinner SC, Gorbach S. Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection. Am J Gastroenterol. 2000;95(12):3482-3489.

Zeitz M, Ullrich R, Schneider T, Kewenig S, Hohloch K, Riecken EO. HIV/SIV enteropathy. Ann N Y Acad Sci. 1998;859:139-148.

Landy J, Gazzard B, Harbord M. Inflammatory bowel disease in HIV seropositive individuals: analysis of a large cohort. Paper presented at: Digestive Disease Week; May 17–22, 2008; San Diego, Calif.

Zar FA, El-Bayoumi E, Yungbluth MM. Histologic proof of acalculous cholecystitis due to Cyclospora cayetanensis. Clin Infect Dis. 2001;33(12):E140-E141.

Palella FJ, Baker RK, Moorman AC, et al.; HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27-34.

Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(5):651-681.

McGovern BH, Ditelberg JS, Taylor LE, et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis. 2006;43(3):365-372.

Sterling RK, Contos MJ, Smith PG, et al. Steatohepatitis: risk factors and impact on disease severity in human immunodeficiency virus/hepatitis C virus coinfection. Hepatology. 2008;47(4):1118-1127.

Sebastiani G, Vario A, Guido M, Alberti A. Performance of noninvasive markers for liver fibrosis is reduced in chronic hepatitis C with normal transaminases. J Viral Hepat. 2008;15(3):212-218.

Bräu N, Fox RK, Xiao P, et al.; North American Liver Cancer in HIV Study Group. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol. 2007;47(4):527-537.

Bruix J, Sherman M Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-1236.

Gray RH, Wawer MJ, Brookmeyer R, et al.; Rakai Project Team. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet. 2001;357(9263):1149-1153.

Celum C, Wald A, Lingappa JR, et al.; Partners in Prevention HSV/HIV Transmission Study Team. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362(5):427-439.

Workowski KA, Berman SM Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006 [published correction appears in MMWR Recomm Rep. 2006;55(36):997]. MMWR Recomm Rep. 2006;55(RR-11):1-94.

Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS. 2004;18(3):541-546.

Fine DM, Perazella MA, Lucas GM, Atta MG. Renal disease in patients with HIV infection: epidemiology, pathogenesis and management. Drugs. 2008;68(7):963-980.

Wyatt CM, Malvestutto C, Coca SG, Klotman PE, Parikh CR. The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis. AIDS. 2008;22(14):1799-1807.

Gupta SK, Eustace JA, Winston JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2005;40(11):1559-1585.

Sweet DE. Metabolic complications of antiretroviral therapy. Top HIV Med. 2005;13(2):70-74.

American Diabetes Association. Standards of medical care in diabetes— 2010 [published correction appears in Diabetes Care. 2010; 33(3):692]. Diabetes Care. 2010;33(suppl 1):S11-S61.

Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 1988;84(3 pt 2):611-616.

Clark RA, Mulligan K, Stamenovic E, et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis. 2001;184(10):1325-1327.

Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165-2174.

Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93(9):3499-3504.

Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008;152(4):582-584.

Herzmann C, Arastéh K. Efavirenz-induced osteomalacia. AIDS. 2009;23(2):274-275.

Bolland MJ, Grey AB, Gamble GD, Reid IR. Low body weight mediates the relationship between HIV infection and low bone mineral density: a meta-analysis. J Clin Endocrinol Metab. 2007;92(12):4522-4528.

Cazanave C, Dupon M, Lavignolle-Aurillac V, et al.; Groupe d'Epidémiologie Clinique du SIDA en Aquitaine. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS. 2008;22(3):395-402.

McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis. 2010;51(8):937-946.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed June 1, 2010.

AIDSinfo
	Telephone: 800-448-0440
	Web site: http://www.aidsinfo.nih.gov
HIV InSite
	Web site: http://hivinsite.ucsf.edu
Johns Hopkins Point-of-Care Information Technology—HIV guide
	Web site: http://www.hopkins-aids.edu
NAM Aidsmap
	Web site: http://www.aidsmap.com