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1032 SECTION 13: Infectious Diseases severe manifestations with these infections. The major concern with Zika virus infection is its potential for teratogenicity.  DIAGNOSIS Obtaining a detailed travel and exposure history and knowing local epidemiologic patterns help in diagnosing arboviral infections. Patients with encephalitis should undergo CT or MRI of the brain. MRI is more sensitive and may show foci of increased signal intensity in the parenchyma. Cerebrospinal fluid typically shows a lymphocytic pleocytosis and a slightly elevated protein level, although these findings are nonspecific. When encephalitis is in the differential diagnosis, save an extra vial of cerebrospinal fluid for further testing, because less common infections are often diagnosed only with stepwise testing after more common causes have been ruled out. Serologic testing is the main method for diagnosis of arboviral infec tions. Viral cultures are labor intensive and technically demanding. Furthermore, patients are viremic for only a few days after the onset of illness. Generally, immunoglobulin M appears within a few days. Patients who are tested very early in the course of illness may have a false-negative result. A presumptive diagnosis of the suspected arboviral infection can be made based on an elevated immunoglobulin M level, and this can be confirmed with an increase in antibody titers between acute and convalescent samples. Many arboviruses are antigenically similar and cross-react on testing. Arboviral infections are reportable to public health authorities in many areas.  TREATMENT Symptomatic management is the mainstay of treatment after excluding other serious, treatable causes of meningitis and encephalitis. Antiviral drugs, interferon, and steroids are not useful. Empiric treatment with acyclovir and antibiotics is appropriate until excluding HSV encephalitis and bacterial meningitis. Anticonvulsant therapy may aid if seizures occur. Hemorrhagic fever is treated with supportive care, with careful fluid management to avoid overload. 14,15 COLORADO TICK FEVER, HEARTLAND VIRUS, AND OTHERS Many rare and novel viruses are either zoonotic or vector borne. Colorado tick fever is an RNA virus transmitted by a tick bite, usually at altitude. The virus then infects erythrocyte precursor cells, and transmission by blood transfusions has been reported. Symptoms are nonspecific, such as fevers, chills, headaches, and myalgias. Rare fatalities have been reported. In 2009 a febrile disease was described in two Missouri farmers and later identified as Heartland virus. 17 It has been reported in the midwestern and southern United States and is thought to be spread by infected ticks, with symptoms similar to bacterial tick-borne diseases such as anaplasmosis or ehrlichiosis. These symptoms include headache, fevers, nausea, and occasionally confusion. A virus with similar geographic distribution, Bourbon virus disease, was described in 2014, when a southern farmer died of complications of a previously unknown viral infection. There is no routine testing available for these viruses, and suspected cases are best referred to local health authorities. The treatment remains supportive, although many also treat for Rocky Mountain spotted fever or other tick-borne bacterial infections when these viruses are suspected. This is because these viral infections have symptoms similar to the tick-borne infections.

suspected cases are best referred to local health authorities. The treatment remains supportive, although many also treat for Rocky Mountain spotted fever or other tick-borne bacterial infections when these viruses are suspected. This is because these viral infections have symptoms similar to the tick-borne infections. When symptoms are nonspecific, it is important to obtain a history on exposures and have an understanding of geographic risks. See Chapter 161, “Zoonotic Infections, ” for more discussion. EBOLA VIRUS DISEASE AND OTHER HEMORRHAGIC FEVERS Viral hemorrhagic fevers are caused by several groups of RNA viruses with varying geographic distributions. These rare diseases elicit fear among the public and healthcare providers because of the lethality and transmission patterns, heightened by outbreaks in Western Africa. Examples include hantavirus pulmonary syndromes, Lassa fever, and perhaps the most notorious, Ebola virus disease. Geographic exposure and contact with an infected traveler are the most important clues to suspecting viral hemorrhagic fevers in an individual patient. Clinical presentation varies between viruses, with some causing relatively minor illness and some with high mortality. Symptoms typically begin with fever, myalgia, and malaise, which then progress to GI and other system involvement. Increased vascular permeability results in hypotension, pulmonary edema, and renal failure. Coagulation defects lead to diffuse hemorrhage, which can be worse in patients with thrombocytopenia or platelet dysfunction, sometimes with extensive bleeding, organ damage, and shock. Ebola and most other viral hemorrhagic fevers can be confirmed with acute serology to identify antibodies or, more commonly, reverse transcriptase polymerase chain reaction identification of the virus that is performed at specialized labs such as the Centers for Disease Control and Prevention. Periodic Ebola virus outbreaks in western Africa have high mortality. The virus is spread through contact with infected body fluids such as bloody vomit and diarrhea, and the lack of personal protective equip ment in developing countries contributes to spread within healthcare facilities. 18 Important aspects of preparing for Ebola and other severe viral hemorrhagic fevers in EDs include screening at triage for illness in travelers returning from areas of current outbreak and rapid initiation of appropriate isolation. Ebola and many other viral hemorrhagic fevers require contact and droplet precautions including full gown, gloves, and facemask with eye protection . Train staff on proper donning and removal of protective equipment to avoid contamination with body fluids. It is important to notify the hospital laboratory to take precautions and to plan for sending specimens to specialized labs. Treatment of Ebola and most other viral hemorrhagic fevers is supportive, with fluids, renal replacement, and respiratory support. Experimental serologic treatments and vaccines are in development. REFERENCES The complete reference list is available online at www.TintinalliEM.com. CHAPTER Human Immunodeficiency Virus Infection Catherine A. Marco Kamna S. Balhara Richard E. Rothman EPIDEMIOLOGY The human immunodeficiency virus (HIV) is the leading cause of infectious disease deaths worldwide. As of 2016, an estimated 36.7 million people worldwide and 1.2 million people in the United States1 have HIV infection or acquired immunodeficiency syndrome (AIDS). Although HIV exists everywhere across the globe, the vast majority of new infec tions (95%) occur in those living in low- and middle-income countries. In sub-Saharan Africa, the world’s most affected region, nearly 1 in every 20 adults is living with HIV .

ave HIV infection or acquired immunodeficiency syndrome (AIDS). Although HIV exists everywhere across the globe, the vast majority of new infec tions (95%) occur in those living in low- and middle-income countries. In sub-Saharan Africa, the world’s most affected region, nearly 1 in every 20 adults is living with HIV . Despite the global burden, the number of new HIV infections and deaths is falling each year. 2 Since the peak of the epidemic in 1996, new HIV infections dropped by nearly 50%; similar worldwide rates of AIDS-related deaths declined by more than 50% since the peak in 2004. Risks associated with acquiring HIV infection include homosexuality or bisexuality, injection drug use, heterosexual exposure, receipt of a blood transfusion prior to 1985, and maternal HIV infection (risk for vertical and horizontal maternal–neonatal transmission). Currently, the majority of HIV cases in the United States (67%) have occurred through men who have sex with men. Heterosexual contact accounts for approximately 24% of transmissions (with recent declines in that group), followed by about 6% associated with injection drug use and 3% Tintinalli_Sec13_p0997-1100.indd 1032 8/2/19 8:12 PM

majority of HIV cases in the United States (67%) have occurred through men who have sex with men. Heterosexual contact accounts for approximately 24% of transmissions (with recent declines in that group), followed by about 6% associated with injection drug use and 3% Tintinalli_Sec13_p0997-1100.indd 1032 8/2/19 8:12 PM CHAPTER 155: Human Immunodeficiency Virus Infection 1033 with male-to-male sexual contact and IV drug use.4 New HIV infection rates continue to rise among young disadvantaged minority populations (many of whom use the ED for both primary and emergency care). African Americans represent 12% of the total U.S. population but almost half (43%) of those with new HIV infections, the highest of any group by race and sex, notably in men having sex with men. Hispanics also have a higher proportion of new infections (26%) than accounted for by their relative size in the population (18%). 5 ED visits by HIVinfected individuals occur at rates higher than the general population due to the characteristics of the populations who use the ED, which are the same groups disproportionately affected by HIV/AIDS. PATHOPHYSIOLOGY HIV is a cytopathic retrovirus that kills infected cells. The virus is labile and neutralized easily by heat and common disinfecting agents such as 50% ethanol, 35% isopropyl alcohol, 0.3% hydrogen peroxide, or a 1:10 solution of household bleach. There are two major subtypes of HIV; HIV-1 is the predominant subtype worldwide and is the cause of AIDS. HIV-2 causes a similar immune syndrome, but exists primarily in western Africa and is infrequent in the United States, but its incidence is growing. The HIV virion is a central RNA molecule and a reverse transcriptase protein surrounded by a core protein encased by a lipid bilayer envelope. After infection, HIV selectively attacks host cells involved in immune function, primarily CD4+ T cells. Within the host cell, HIV-encoded RNA uses reverse transcription to enter into DNA, aided by the enzyme reverse transcriptase. The viral genome integrates into the host genome, where it may lie dormant or be transcribed and translated to produce virally encoded proteins and new HIV virions. As a result of infection, immunologic abnormalities eventually occur, including lymphopenia, qualitative CD4+ T-cell function defects, and autoimmune phenomena. Defects in cellular immunity ultimately result in a variety of opportunistic infections and neoplasms. HIV exists in saliva, urine, cerebrospinal fluid (CSF), pus, brain, tears, alveolar fluid, synovial fluid, and amniotic fluid. Transmission of HIV occurs through semen, vaginal secretions, blood or blood products, and breast milk, and in utero by transplacental transmission. Transmission of HIV infection does not occur with casual contact. There is only one documented confirmed case of transmission from healthcare worker to patient in the United States, which involved an infected dentist in Florida who transmitted the virus to six patients; as of 2018, there were 58 cases of confirmed patient–to–healthcare worker transmissions, with the vast majority occurring before 1991 (see later discussion regarding occupational exposure). NATURAL HISTORY AND CLINICAL STAGES OF HIV INFECTION Stage 1 or acute HIV infection occurs 2 to 4 weeks after infection with HIV . Also called acute retroviral syndrome, this is the initial response to infection, causing symptoms in the majority of those infected. The clinical presentation is nonspecific, resembling a flulike or mononucleosislike syndrome; the diagnosis is missed in about 75% of cases.

ccurs 2 to 4 weeks after infection with HIV . Also called acute retroviral syndrome, this is the initial response to infection, causing symptoms in the majority of those infected. The clinical presentation is nonspecific, resembling a flulike or mononucleosislike syndrome; the diagnosis is missed in about 75% of cases. Symptoms of acute HIV infection typically occur within 1 month of becoming infected, may last for 2 to 10 weeks, and include fever (>90%), fatigue (70% to 90%), pharyngitis (>70%), rash (40% to 80%), headache (30% to 70%), and lymphadenopathy (40% to 70%); other reported symptoms are weight loss, headache, and diarrhea. 7 Seroconversion and detectable antibody response to HIV usually occur 3 to 8 weeks after infec tion, although delays can be up to 11 months. Stage 2 of HIV infection is the period of clinical latency or HIV inactivity during which time patients generally have no complaints or find ings on physical examination except for possible persistent generalized lymphadenopathy (enlarged lymph nodes in at least two noncontiguous sites other than inguinal nodes). For patients not taking any medication, the median incubation time from exposure to the development of AIDS is estimated at 10 years for adults; shorter incubation periods occur in untreated infants and older adults. Virologic studies of patients during this period suggest that a steady state of HIV replication and CD4+ T-cell death and replacement exists until increased levels of HIV rep lication occur. Variables most predictive of disease stage are viral load and CD4+ T-cell counts, with a steeper decline in CD4+ T-cell count and a higher viral burden associated with more rapid progression and more adverse outcomes. Other non–HIV-related factors, such as age and malignancy, also impact disease progression. Toward the end of the clinical latency period, as the CD4 count begins to drop and viral load starts to rise, patients begin to develop symptomatic infection characterized by conditions that are more common and more severe in the presence of HIV infection, but are not AIDS-indicator conditions. These include thrush, persistent vulvovaginal candidiasis, peripheral neuropathy, cervical dysplasia, recurrent herpes zoster, and idiopathic thrombocytopenic purpura. Stage 3 of HIV infection has either laboratory markers of severe immunosuppression (CD cell counts <200 cells/mm 3) or occurrence of one of any opportunistic infections or AIDS-defining illnesses (Table 155-1). DIAGNOSIS Early diagnosis of acute HIV infection allows the benefit of limiting risk of unrecognized HIV and also initiation of antiretroviral therapy (ART), which reduces symptoms and slows disease progression. Acute HIV is the time from HIV transmission to seroconversion.

ons or AIDS-defining illnesses (Table 155-1). DIAGNOSIS Early diagnosis of acute HIV infection allows the benefit of limiting risk of unrecognized HIV and also initiation of antiretroviral therapy (ART), which reduces symptoms and slows disease progression. Acute HIV is the time from HIV transmission to seroconversion. Diagnosis of acute HIV infection can now be made with newer TABLE 155-1 Stage 3 AIDS-Defining Opportunistic Illnesses in HIV Infection •  Bacterial  infections, multiple or recurrent* •  Candidiasis  of bronchi, trachea, or lungs •  Candidiasis  of esophagus •  Cervical  cancer, invasive† •  Coccidioidomycosis,  disseminated or extrapulmonary •  Cryptococcosis,  extrapulmonary •  Cryptosporidiosis,  chronic intestinal (>1 month in duration) •  Cytomegalovirus  disease (other than liver, spleen, or nodes), onset at age >1 month •  Cytomegalovirus  retinitis (with loss of vision) •  Encephalopathy  attributed to HIV •   Herpes simplex: chronic ulcers (>1 month in duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month) •   Histoplasmosis, disseminated or extrapulmonary •   Isosporiasis, chronic intestinal (>1 month in duration) •   Kaposi’s sarcoma •   Lymphoma, Burkitt’s (or equivalent term) •   Lymphoma, immunoblastic (or equivalent term) •   Lymphoma, primary, of brain •   Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex* •   Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary •   Mycobacterium tuberculosis of any site, pulmonary,† disseminated, or extrapulmonary •   Mycobacterium, other species or unidentified species, disseminated or extrapulmonary •   Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia •   Pneumonia, recurrent† •   Progressive multifocal leukoencephalopathy •   Salmonella septicemia, recurrent •   Toxoplasmosis of brain, onset at age >1 month •   Wasting syndrome attributed to HIV Abbreviations: AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency syndrome. *Only among children aged <13 years. (Centers for Disease Control and Prevention: 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Morbid Mortal Wkly Rep 1994;43[No. RR-12].) †Only among adults and adolescents aged >13 years. (Centers for Disease Control and Prevention: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbid Mortal Wkly Rep 1992;41[No. RR-17].) Tintinalli_Sec13_p0997-1100.indd 1033 8/2/19 8:12 PM

among adults and adolescents aged >13 years. (Centers for Disease Control and Prevention: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbid Mortal Wkly Rep 1992;41[No. RR-17].) Tintinalli_Sec13_p0997-1100.indd 1033 8/2/19 8:12 PM 1034 SECTION 13: Infectious Diseases fourth-generation HIV tests (see later discussion). Other methods for earlier detection of HIV-1 include techniques to detect DNA, RNA, or HIV antigens, although these tests are not always available in the ED. Mean times from transmission to detection are shortest for viral load (17 days), followed by p24 antigen (22 days), enzyme-linked immunosorbent assay positivity (25 days), and Western blot positivity (31 days). For patients with suspected acute HIV that has not been confirmed (i.e., those with a high-risk profile presenting with fever of unknown origin and/or a syndrome suspicious for acute seroconversion), counseling and urgent referral to outpatient follow-up are best.  HIV TESTING METHODS HIV infection diagnosis uses identification of HIV nucleic acid, detec tion of viral-specific antigen, detection of antibodies to HIV , and isolation of the virus by culture (now rarely used in practice). The most commonly used testing method for HIV is detection of antibodies to the virus. These newer testing methods revolutionized the ability of ED providers to diagnose patients with HIV . Previously, HIV testing involved sequential use of an enzyme-linked immunosorbent assay, followed by a Western blot assay. Enzyme-linked immunosorbent assay is approximately 99% specific and 98.5% sensitive; Western blot testing is nearly 100% sensitive and specific if performed under ideal laboratory conditions. Enzyme-linked immunosorbent assay detects specific serum antibodies to HIV antigens. Western blot assay detects HIV antibodies to viral antigens. Reasons for indeterminate test results include early seroconversion, cross-reacting antibodies, pregnancy, presence of an autoimmune disease, or technical errors.  RAPID HIV TESTS There are numerous rapid HIV tests approved for use by the U.S. Food and Drug Administration, usable as single-use disposable tests of blood, serum, plasma, or oral fluid. 9 Sensitivity and specificity are comparable with those of standard serologic testing, and minimal training is required for administration. Relay any point-of-care results to the patient as preliminary positive if reactive, and confirm the results with Western blot testing. Negative test results may miss patients in the window period before seroconversion; this requires a repeat test at 3 months.  THE HIV TESTING ALGORITHM The Centers for Disease Control and Prevention recommends laboratory testing approaches for HIV . 10 The algorithm calls for automated testing for antibody to HIV-1 and HIV-2 simultaneously with detection of HIV-1 p24 antigen, permitting detection of acute infections. In instances where this set of tests is negative, no further testing occurs, and the patient is counseled that he or she tested negative. For those with posi tive results, follow-up testing differentiates HIV-1 and HIV-2. In cases where the differentiation test is negative, a nucleic acid amplification test confirms acute seroconversion. Turnaround time for the combined assay and HIV-1/2 differentiation assay is about 60 minutes. Turnaround time for confirmatory testing with nucleic acid amplification can take up to a few days. This new algorithm allows better early detec tion; ED-based studies show this is feasible and will detect new, acutely infected patients. 11-13  CD4+ T-CELL COUNTS CD4+ T-cell counts of <200 cells/mm3 and a viral load of >50,000 copies/ mm3 are associated with increased risk of AIDS-defining illnesses.

to a few days. This new algorithm allows better early detec tion; ED-based studies show this is feasible and will detect new, acutely infected patients. 11-13  CD4+ T-CELL COUNTS CD4+ T-cell counts of <200 cells/mm3 and a viral load of >50,000 copies/ mm3 are associated with increased risk of AIDS-defining illnesses. When this information is unavailable or the stage of disease is unknown, use the total lymphocyte count to approximate the CD4+ T-cell count. In a recent ED study, a total lymphocyte count <1700 cells/mm 3 had a sensitivity of 95% for a CD4 count of <200 cells/mm 3.13  HIV TESTING PRACTICES IN THE ED Historically, HIV testing challenges in the ED were time limitations, difficulty with follow-up, confidentiality requirements, costs, and questions regarding reimbursement. Advances in testing technologies coupled with new policy guidelines address these barriers. In 2006, the Centers for Disease Control and Prevention recommended testing guidelines that included an opt-out approach to consent, meaning that HIV testing can be performed after notifying the patient that testing will be done (without separate written consent) unless they explicitly decline. 14 Further, the U.S. Preventive Services Task Force gave a “Grade A ” recommendation for routine HIV screening for all people age 15 to 65 years, as well as younger adolescents and older adults who are at an increased risk for HIV infection and all pregnant women, including those in labor whose HIV status is unknown. The Patient Protection and Affordable Care Act requires new insurance policies to pay for preventive services with “Grade A ” recommendation. The American College of Emergency Physicians supports ED HIV testing based on clinical need and supports screening with caveats. While overall rates of HIV testing in EDs in the United States in the early part of the century were low (approximately 0.2% of all ED visits), programs are increasing, particularly in urban and/or academic centers; in some areas, increases in testing paralleled declines in undiagnosed HIV and control of the epidemic. 15 Ongoing research targets best ED testing approaches (e.g., nontargeted universal vs. targeted), with local prevalence playing a key role in the screening plan chosen. CLINICAL FEATURES AND TREATMENT  INITIAL CARE: GENERAL CONSIDERATIONS The spectrum of disease caused by HIV infection varies, from those coming to the ED with asymptomatic infection for symptoms unrelated to HIV disease, to symptomatic patients seeking care from involvement of virtually any organ system and with multiple coexisting symptoms. Maintain confidentiality regarding HIV-related diagnoses in the ED. Begin care without discrimination and without assuming any illness trajectory unless advance directives, including cardiopulmonary resus citation, are already in place. If friends or family accompany the patient to the ED, first ask the patient about privacy issues before beginning any conversations. Always use blood and body fluid precautions during care (in some hospitals, this is termed universal or standard precautions ). Healthcare workers can be exposed to the blood and body fluids of HIV-infected patients or patients at high risk of harboring the HIV virus. ED-based studies show that many patients have unsuspected HIV infection and that seropositivity cannot be predicted accurately, even after assessment of risk factors. See Chapter 163, “Occupational Exposures, Infection Control, and Standard Precautions. ” A basic history and physical examination help to identify the clinical stage of disease and to direct attention to the most likely complica tions. Obtain a thorough report detailing past and current medications including ART, previous infections, and the patient’s ability to perform activities of daily living.

tions. ” A basic history and physical examination help to identify the clinical stage of disease and to direct attention to the most likely complica tions. Obtain a thorough report detailing past and current medications including ART, previous infections, and the patient’s ability to perform activities of daily living. The exam seeks findings of organ involvement related to the chief complaint and features that might assist with staging such as oral candidiasis, skin lesions, temporal wasting, and dementia. Diagnosis and initial care seek to recognize infection (when not previously diagnosed), assess the severity of disease, identify specific organ(s) involved, and institute therapy. Consultation with an infectious disease specialist and others with expertise in HIV infection is often neces sary to provide proper therapy and disposition. Disposition decisions are based on the need for inpatient evaluation or management and the patient’s ability to function as an outpatient, the latter often being driven by oral intake and ambulation ability and the availability of appropriate medical follow-up. Healthcare, family resources, and case management can aid decision making about appropriate site for care. Systemic symptoms such as fever, weight loss, and malaise are common in HIV-infected patients and account for the majority of HIV-related ED presentations. In the ED, look for systemic infec tion, malignancy, drug toxicity, or metabolic abnormalities. Often, this includes assessing serum electrolytes with renal function, CBC, liver function studies, blood cultures, urinalysis and urine culture, hepatic function tests, and chest radiograph; use serologic testing for syphilis, cryptococcosis, toxoplasmosis, cytomegalovirus infection, and coccidioidomycosis more selectively. Lumbar puncture occurs after Tintinalli_Sec13_p0997-1100.indd 1034 8/2/19 8:12 PM

on studies, blood cultures, urinalysis and urine culture, hepatic function tests, and chest radiograph; use serologic testing for syphilis, cryptococcosis, toxoplasmosis, cytomegalovirus infection, and coccidioidomycosis more selectively. Lumbar puncture occurs after Tintinalli_Sec13_p0997-1100.indd 1034 8/2/19 8:12 PM CHAPTER 155: Human Immunodeficiency Virus Infection 1035 neuroimaging if headache, altered sensorium, visual change, or other focal neurologic symptoms or signs are present. When treating the febrile ill-appearing HIV patient, provide fluid resuscitation and prompt empiric antibiotics, and admit for further evaluation and management. Outpatient evaluation and treatment are indicated only when all of the following conditions are met: the source of the fever does not dictate admission, the patient is able to function adequately at home (e.g., can maintain sufficient oral intake), and timely medical follow-up can be arranged.  HIV STAGE AND CAUSES OF FEVER Infections are the most common cause of hospitalization among HIVinfected persons. In HIV-infected persons without obvious localizing signs or symptoms, sources of fever vary by stage of disease. Patients with CD4+ T-cell counts of >500 cells/mm 3 generally have causes of fever similar to those in nonimmunocompromised patients, whereas those with CD4+ T-cell counts between 200 and 500 cells/mm 3 are more likely to have infections that are associated with early immune compromise, including bacterial pneumonia, herpes zoster, and tuber culosis. For patients with CD4+ T-cell counts of <200 cells/mm 3, the most common causes of fever without obvious localizing findings are early Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii ); central line infection; infection with Mycobacterium avium complex, Mycobacterium tuberculosis , or cytomegalovirus; drug fever; and sinusitis. Other causes of fever include endocarditis, lym phoma, and infection with Histoplasma capsulatum or Cryptococcus neoformans. Disseminated M. avium Complex Infection Disseminated M. avium complex infection occurs predominantly in patients with CD4+ T-cell counts of ≤100 cells/mm 3 who are not on ART or azithromycin prophylaxis. Persistent fever and night sweats are typical symptoms. Associated symptoms include weight loss, diarrhea, malaise, and anorexia. Dis semination to the bone marrow, liver, and spleen results in anemia and elevated alkaline phosphatase levels. Diagnose this with acid-fast stain of stool or other body fluids or by blood culture. Cultures using the lysiscentrifugation method are more sensitive for M. avium complex (and histoplasmosis) and aid diagnosis in patients with late-stage disease and fever of unknown origin. Treatment for M. avium complex reduces bacteremia and improves symptoms but does not eradicate disease; therapy starts with clarithromycin combined with ethambutol and rifabutin. Azithromycin is an alternative therapy. Immune Reconstitution Inflammatory Syndrome Immune reconstitution inflammatory syndrome mimics an autoimmune event, with lymphadenitis, fever, and other symptoms starting weeks to months after beginning ART, often during tuberculosis therapy. There is no definitive diagnostic test for this condition. Treatment guidelines advise continuing ART; use nonsteroidal anti-inflammatory agents for mild to moderate cases; in severe cases, use corticosteroids (prednisone 1 to 2 milligrams/kg or equivalent for 1 to 2 weeks). Add the appropriate antimicrobials if there is a known or suspected infection. Cytomegalovirus Cytomegalovirus is a common cause of serious opportunistic viral disease in HIV-infected patients. Disseminated dis ease involves the GI, pulmonary, and central nervous systems.

milligrams/kg or equivalent for 1 to 2 weeks). Add the appropriate antimicrobials if there is a known or suspected infection. Cytomegalovirus Cytomegalovirus is a common cause of serious opportunistic viral disease in HIV-infected patients. Disseminated dis ease involves the GI, pulmonary, and central nervous systems. The most important manifestation is retinitis (see later section, “Cytomegalovirus Retinitis”). Treatment is with foscarnet or ganciclovir. Oral ganciclovir is a prophylaxis agent (Table 155-2). Endocarditis Fever in injection drug users should trigger suspicion for infective endocarditis, which often has a nonspecific presentation in the ED (see Chapter 156, “Endocarditis”). Most ED physicians admit febrile injection drug users while awaiting the results of blood cultures and echocardiography given the high morbidity and mortality coupled with the difficulties encountered with outpatient follow-up in the drug user population. Neoplasm and Drug Fever Noninfectious causes of fever in HIV patients include neoplasm and drug fever. Non-Hodgkin’s lymphoma is the most frequently occurring neoplasm, characterized by high-grade, rapidly growing mass lesions. New CNS symptoms, particularly a change in mental status in the presence of fever, require neuroimaging. Definitive diagnosis of non-Hodgkin’s lymphoma requires biopsy. Radiotherapy and chemotherapy are effective treatment regimens. Drug fever may be secondary to injection drug abuse or adverse drug reactions (see later discussion). NEUROLOGIC COMPLICATIONS Neurologic disease in HIV patients may be related to opportunistic infections, neoplasms, impact of HIV infection on CNS, or HIV treat ment itself. Presenting symptoms may include seizures, altered mental status, headache, meningismus, and focal neurologic deficits. Patients with HIV presenting to the ED with headache, seizure, altered mental status, or focal neurologic deficits with or without fever should have neuroimaging, especially in patients with CD4 count <200 cells/mm 3. Although noncontrast CT is typically the first imaging modality used in the ED, contrast-enhanced CT and MRI may be needed if CT findings are equivocal or negative. If no mass lesion exists, lumbar puncture follows to assess or obtain the following: CSF pressures, WBC count and differential, protein and glucose concentra tions, Gram staining, India ink staining, bacterial culture, mycobacterial culture, fungal culture, toxoplasmosis and cryptococcosis antigen assays, coccidioidomycosis titer, and polymerase chain reaction assays for JC virus, Epstein-Barr virus, cytomegalovirus, Toxoplasma gondii , herpes simplex virus types 1 and 2, and varicella-zoster virus. Save additional CSF in case further testing needs arise later. Consider toxoplasmosis serology and QuantiFERON tuberculosis testing too. Even if the ED evaluation is unrevealing, admit all patients with new or changed neu rologic signs or symptoms.  HIV-ASSOCIATED NEUROCOGNITIVE DISORDER HIV-associated neurocognitive disorder (also referred to as HIV encephalopathy, HIV-associated dementia, or AIDS dementia complex) is a progressive, subacute disorder heralded by subtle impairment of recent memory, cognitive deficits, and behavioral disturbances. Up to 50% of patients on ART have some form of HIV-associated neurocognitive disorder. 16 Many patients may exhibit only mild deficits. However, inadequately treated patients may progress to the most advanced form of HIV-associated neurocognitive disorder, HIV-associated dementia, and demonstrate moderate to severe cognitive impairment with behavioral changes. 17 HIV-associated dementia is a diagnosis of exclusion, once MRI and lumbar puncture have ruled out other pathologies.

ated patients may progress to the most advanced form of HIV-associated neurocognitive disorder, HIV-associated dementia, and demonstrate moderate to severe cognitive impairment with behavioral changes. 17 HIV-associated dementia is a diagnosis of exclusion, once MRI and lumbar puncture have ruled out other pathologies. New signs or symptoms in a patient with known HIV-associated dementia should prompt workup for other CNS processes. ART is the most effective treatment for HIV-associated dementia.  TOXOPLASMIC ENCEPHALITIS Since the introduction of ART, toxoplasmosis encephalitis remains the most commonly reported neurologic opportunistic infection. 18 It occurs most commonly in patients with CD4+ cell counts <100 cells/mm 3 as latent bradyzoites acquired early in life reactivate. Symptoms may include headache, fever, focal neurologic deficits, altered mental status, seizures, and behavioral changes. On unenhanced CT scan, toxoplasmosis typically appears as multiple subcortical lesions with a predilection for the basal ganglia and corticomedullary junction. Contrast-enhanced CT scan typically shows multiple ring-enhancing lesions with surrounding areas of edema. MRI is more sensitive than contrast-enhanced CT scan in detecting toxoplasmosis. Consider primary CNS lymphoma as another potential cause or mimic. CSF may not be available since many patients are at risk for herniation; polymerase chain reaction, although highly specific (100%), is not sufficiently sensitive (50% to 80%) to detect T. gondii in CSF . Patients with positive serology (immunoglobulin G) in combination with symptoms and imaging suggestive of T. gondii should be treated. Admit patients with suspected toxoplasmosis and treat with a com bination of IV pyrimethamine plus sulfadiazine plus leucovorin (folinic acid). Clindamycin is a substitute for sulfadiazine. Some trials show trimethoprim-sulfamethoxazole may have equal efficacy 19 (Table 155-2). Corticosteroids can aid in treating any mass effect, but discontinue these as soon as possible. For patients responsive to toxoplasmosis therapy, use chronic suppressive therapy with oral sulfamethoxazole-trimethoprim; Tintinalli_Sec13_p0997-1100.indd 1035 8/2/19 8:12 PM

xazole may have equal efficacy 19 (Table 155-2). Corticosteroids can aid in treating any mass effect, but discontinue these as soon as possible. For patients responsive to toxoplasmosis therapy, use chronic suppressive therapy with oral sulfamethoxazole-trimethoprim; Tintinalli_Sec13_p0997-1100.indd 1035 8/2/19 8:12 PM 1036 SECTION 13: Infectious Diseases (Continued) TABLE 155-2 Treatment Recommendations for Common Human Immunodeficiency Virus–Related Infections ( Continued) Organ System Infection Therapy Systemic Mycobacterium avium-intracellulare Clarithromycin, 500 milligrams PO twice a day and Ethambutol, 15 milligrams/kg PO once a day and Rifabutin, 300 milligrams/kg PO once a day (addition may improve survival and decrease risk of macrolide resistance) CMV infection (GI) Ganciclovir, 5 milligrams/kg IV twice a day for 3–4 wk Foscarnet, 90 milligrams/kg every 12 h for 3–4 wk Pulmonary

ams PO twice a day and Ethambutol, 15 milligrams/kg PO once a day and Rifabutin, 300 milligrams/kg PO once a day (addition may improve survival and decrease risk of macrolide resistance) CMV infection (GI) Ganciclovir, 5 milligrams/kg IV twice a day for 3–4 wk Foscarnet, 90 milligrams/kg every 12 h for 3–4 wk Pulmonary Pneumocystis jirovecii (Pneumocystis carinii) pneumonia Trimethoprim-sulfamethoxazole (TMP-SMZ), 5 milligrams/kg (of TMP component) every 8 h for 21 d Clindamycin 600 milligrams every 8 h plus primaquine 15–30 milligrams once daily for 21 d Note: Other second-line options are available for those who are allergic. If partial pressure of arterial oxygen is <70 mm Hg or alveolar-arterial gradient is >35 mm Hg, then add: Prednisone, 40 milligrams twice a day for 5 d, then 40 milligrams once a day for 5 d, then 20 milligrams once a day for 11 d Mycobacterium tuberculosis infection * Isoniazid, 5 milligrams/kg PO once a day and Rifampin, 10 milligrams/kg (600 milligrams max) PO once a day or rifabutin 5 milligrams/kg PO once a day (for person on PIsw, NNRTIs, integrase inhibitors, or methadone) and Pyrazinamide, 15–30 milligrams/kg (2 grams max) PO once a day and Ethambutol, 15–20 milligrams/kg (1.6 grams max) PO once a day and Pyridoxine (vitamin B 6) 60 milligrams PO once daily Note: Treatment duration determined by site of disease and response to therapy. CNS Toxoplasmosis† Pyrimethamine, 200-milligram loading dose PO followed by 50–75 milligrams PO once a day for 6–8 wk and Sulfadiazine, 1–1.5 grams PO every 6 h for 6–8 wk and Leucovorin, 10–25 milligrams once a day Cryptococcosis‡ Amphotericin B, 0.7 milligram/kg IV once a day for 2 wk and Flucytosine, 25 milligrams/kg IV four times a day for 2 wk then Fluconazole, 400 milligrams/d PO for 8–10 wk Ophthalmologic CMV infection (retinitis)§ Valganciclovir, 900 milligrams PO twice a day for 14–20 d of induction therapy, then 900 milligrams PO daily for maintenance therapy IV ganciclovir and foscarnet are now rarely used because of need for permanent indwelling catheter and avail ability of safer options (valganciclovir) GI Candidiasis (thrush—limited to mouth) Clotrimazole, 10-milligram troches 5 times a day for 7–14 d Nystatin, 500,000 units 5 times a day, gargle for 7–14 d Esophagitis (primarily Candida) Fluconazole, 200–400 milligrams/d PO Salmonellosis† Ciprofloxacin, 500 milligrams PO twice a day for 2–4 wk Note: Modify according to susceptibilities when available. Cryptosporidiosis No known effective cure; best results with highly active antiretroviral therapy and symptomatic treatment Cutaneous Herpes simplex Acyclovir, 400 milligrams PO 3 times a day for 7–10 d Famciclovir, 500 milligrams 3 times a day for 7–10 d Valacyclovir, 1 gram PO twice a day for 7 d or for severe disease Acyclovir, 5–10 milligrams/kg IV every 8 h for 7 d Tintinalli_Sec13_p0997-1100.indd 1036 8/2/19 8:12 PM

ptomatic treatment Cutaneous Herpes simplex Acyclovir, 400 milligrams PO 3 times a day for 7–10 d Famciclovir, 500 milligrams 3 times a day for 7–10 d Valacyclovir, 1 gram PO twice a day for 7 d or for severe disease Acyclovir, 5–10 milligrams/kg IV every 8 h for 7 d Tintinalli_Sec13_p0997-1100.indd 1036 8/2/19 8:12 PM CHAPTER 155: Human Immunodeficiency Virus Infection 1037 this can also be prophylaxis in patients with positive toxoplasmosis serologic test results and CD4+ T-cell counts of <100 cells/mm3.  CRYPTOCOCCAL MENINGITIS Cryptococcal infection occurs most commonly in patients with CD4+ counts of <50 cells/mm 3. The most common presenting signs are fever and headache, followed by nausea, altered mentation, and focal neuro logic deficits. Presentation may be subacute, and meningismus is uncommon. Although communicating hydrocephalus with high intracranial pressure may develop, CT imaging may be normal or nonspecific. Diagnosis of CNS cryptococcal infection in HIV patients relies on CSF cryptococcal antigen testing (92% sensitive and 83% specific), fun gal culture (95% to 100% sensitive), or staining with India ink (60% to 80% sensitive). Serum cryptococcal antigen testing helps but has lower sensitivity than CSF testing (approximately 95%). The expected CSF WBC count elevation is often absent in patients with AIDS, although increased opening pressure is common and drainage aiming to reduce pressure by 50% or to less than 20 cm H 2O is best. Patients with CNS cryptococcosis require hospital admission and IV amphotericin B and oral flucytosine for 14 days, followed by fluconazole for 8 weeks to clear the CSF (Table 155-2). Long-term maintenance therapy follows initial treatment.  OTHER NEUROLOGIC DISORDERS Cytomegalovirus may cause encephalitis, radiculomyelitis, or mononeuritis multiplex, with nonspecific periventricular enhancement on neuroimaging and highly sensitive and specific CSF polymerase chain reaction. Evaluate patients with cytomegalovirus encephalitis for con current retinitis. Ganciclovir is a mainstay of treatment. Reactivation of the JC virus may lead to progressive multifocal leukoencephalopathy, with focal neurologic deficits developing over weeks, although acute cases may mimic stroke, and initiation of ART is key to management. Multifocal demyelinating lesions exist on imaging; sensitivity of CSF polymerase chain reaction for JC virus is variable. The incidence of primary CNS lymphoma has declined since the introduction of ART; once diagnosed, prognosis is poor, with a median survival of 2 months. CNS lymphoma may present with nonspecific symptoms or focal deficits, without fever. Postcontrast imaging may demonstrate a ring-enhancing lesion, and presence of Epstein-Barr virus in CSF is highly sensitive. Other considerations in the presence of neurologic symptoms include bacterial meningitis, herpes simplex virus infection, neurosyphilis, tuberculosis (tuberculoma or meningitis, treated as systemic tuberculosis), cerebrovascular accidents, and metabolic encephalopathies. Neuropsychiatric disturbances may occur from HIV therapies including ART, such as efavirenz, or drugs to treat opportunistic infections, such as ganciclovir. Peripheral neuropathies are common in HIV patients, either because of chronic HIV infection, known as HIV-associated distal sensory polyneuropathy, or treatment-related toxicity related to ART; change in treatment regimen may address the latter. Reserve opioids for short durations and severe pain; topical capsaicin or lamotrigine aid often. Autonomic neuropathies and inflammatory demyelinating polyneuropathies may also occur. PSYCHIATRIC DISORDERS HIV infection may cause CNS and metabolic disturbances that can produce psychiatric symptoms.

address the latter. Reserve opioids for short durations and severe pain; topical capsaicin or lamotrigine aid often. Autonomic neuropathies and inflammatory demyelinating polyneuropathies may also occur. PSYCHIATRIC DISORDERS HIV infection may cause CNS and metabolic disturbances that can produce psychiatric symptoms. HIV infection is also a psychosocial stressor and may contribute to social isolation, poverty, and hopelessness. In the ED, search for underlying organic causes, such as delirium, demen tia, neurologic infection or mass, electrolyte abnormality, medication adverse effect, trauma, or other organic etiology of depression. Patients with AIDS psychosis typically develop hallucinations, delusions, or other behavioral changes. Depression is common during all phases of HIV infection. 21-23 Antidepressant therapy is often started if symptoms of depression continue for >2 weeks and with close monitoring for side effects. Patients with suicidal ideation or profound dysfunction may require inpatient psychiatric management. An increased incidence of mania occurs in both the early and late stages of HIV infection. Late-stage mania is closely associated with dementia and carries a poor prognosis. If danger exists, use physi cal restraints or acute pharmacologic intervention. Other psychiatric manifestations may occur with increased incidence in the HIV-infected population, including schizophrenia, bipolar disorder, posttraumatic stress disorder, and personality disturbance. Nearly 50% of those with HIV infection also have a history of substance abuse. 24 Depression and psychotic symptoms are more prevalent among patients with substance abuse. ED management includes identification and outpatient referral to integrated substance abuse and psychiatric resources. Some antiretroviral agents have interactions with buprenorphine and methadone requiring dosage modifications of the latter two agents. TABLE 155-2 Treatment Recommendations for Common Human Immunodeficiency Virus–Related Infections ( Continued) Organ System Infection Therapy Herpes zoster Acyclovir, 800 milligrams PO 5 times a day for 7–10 d Famciclovir, 500 milligrams PO 3 times a day for 7–10 d Valacyclovir, 1 gram PO 3 times a day for 7–10 d or for ocular or disseminated disease Acyclovir, 5–10 milligrams/kg PO every 8 h for 5–7 d Candida or Trichophyton infection Topical clotrimazole 2 or 3 times a day for 3 wk Nystatin, 500,000 units 5 times a day, gargle for 7–14 d Fluconazole 100–200 milligrams PO every day for 7–14 d Note: Medication dose and duration may need to be adjusted based on drug–drug interactions, renal and/or liver functions based on individual patient, and concomitant medications. Please check with your local pharmacist prior to using these doses. Abbreviations: CMV = cytomegalovirus; NNRTIs = nonnucleoside reverse transcriptase inhibitors. *Specific drug regimen must be adjusted if patient is receiving highly active antiretroviral therapy. †Maintenance therapy required. ‡Maintenance therapy required; may be discontinued if CD4+ T-cell count is >150 cells/mm 3 for >16 wk. §Maintenance therapy required until CD4+ T-cell count is >150 cells/mm 3. Tintinalli_Sec13_p0997-1100.indd 1037 8/2/19 8:12 PM

patient is receiving highly active antiretroviral therapy. †Maintenance therapy required. ‡Maintenance therapy required; may be discontinued if CD4+ T-cell count is >150 cells/mm 3 for >16 wk. §Maintenance therapy required until CD4+ T-cell count is >150 cells/mm 3. Tintinalli_Sec13_p0997-1100.indd 1037 8/2/19 8:12 PM 1038 SECTION 13: Infectious Diseases OPHTHALMIC COMPLICATIONS Cytomegalovirus retinitis and herpes zoster ophthalmicus must be recognized by the emergency physician and have specialty consultation sought. Other manifestations include HIV retinopathy, charac terized by non–vision-threatening retinal cotton-wool spots (seen in >50% of patients with advanced HIV), retinal hemorrhages, and microaneurysms. Syphilis may lead to ocular complications, and Toxoplasma retinochoroiditis (whitish retinal lesions without hemor rhage), Cryptococcus chorioretinitis (multiple discrete yellowish spots on choroid and retina), and pneumocystis choroiditis (multiple pale yellow-white choroidal spots) may also occur. Treatment for these entities is the same as for systemic infection.  CYTOMEGALOVIRUS RETINITIS Cytomegalovirus retinitis ( Figure 155-1) is the most serious ocular opportunistic infection and is the leading cause of blindness in AIDS patients. Since the advent of newer ART, the incidence of cytomegalovirus infection has decreased. 25 Retinitis may be asymptomatic early but may present with changes in visual acuity, visual field cuts, photophobia, flashes, floaters, eye redness, or eye pain. Findings on indirect ophthal moscopy are fluffy white perivascular lesions with areas of hemorrhage, which may be confused with benign cotton-wool spots. Request emer gent ophthalmologic consultation early in suspected cytomegalovirus retinitis. Systemic treatment, often with oral valganciclovir, is a first-line treatment; those with sight-threatening lesions near the optic nerve or macula also need intravitreal ganciclovir.  HERPES ZOSTER OPHTHALMICUS Herpes zoster ophthalmicus (see Chapter 241, “Eye Emergencies”) usually presents with paresthesia and discomfort in the distribution of cranial nerve V 1 (ophthalmic branch), followed by the appearance of the typical zoster skin rash. Ocular complications include conjunctivi tis, episcleritis, iritis, keratitis, secondary glaucoma, and, rarely, retinal necrosis. Early recognition and treatment can prevent ocular damage. PULMONARY COMPLICATIONS Pulmonary abnormalities in HIV-infected patients include a wide vari ety of conditions including community-acquired bacterial pneumonia, P . jirovecii pneumonia (PCP), tuberculosis, cytomegalovirus infection, cryptococcosis, histoplasmosis, chronic obstructive pulmonary disease, lymphoid interstitial pneumonia, and neoplasms. The most common cause of pneumonia in HIV-infected patients in the United States and Western Europe is Streptococcus pneumoniae, followed by PCP and tuberculosis. 26 Pulmonary radiographic findings are helpful in deter mining likely causes ( Table 155-3). Admit patients with new-onset or profound pulmonary symptoms, especially in the presence of hypox emia or altered mental status. In patients with known existing pulmo nary involvement, disposition and care decisions are based on change from baseline, the effectiveness of ongoing or previous treatment, ability to adhere to therapy, and the ability to obtain outpatient follow-up.

, especially in the presence of hypox emia or altered mental status. In patients with known existing pulmo nary involvement, disposition and care decisions are based on change from baseline, the effectiveness of ongoing or previous treatment, ability to adhere to therapy, and the ability to obtain outpatient follow-up. TABLE 155-3 Chest Radiographic Abnormalities: Differential Diagnosis in the Patient With Acquired Immunodeficiency Syndrome Finding Causes Diffuse interstitial infiltration Pneumocystis jirovecii infection Cytomegalovirus infection Mycobacterium tuberculosis infection Mycobacterium avium-intracellulare complex infection Histoplasmosis Coccidioidomycosis Lymphoid interstitial pneumonitis Focal consolidation Bacterial pneumonia Mycoplasma pneumoniae infection P. jirovecii infection M. tuberculosis infection M. avium-intracellulare complex infection Malignancy Nodular lesions Lymphocytic interstitial pneumonitis Kaposi’s sarcoma M. tuberculosis infection M. avium-intracellulare complex infection Fungal infection Toxoplasmosis Cavitary lesions P. jirovecii infection M. tuberculosis infection Bacterial infection Fungal infection Adenopathy Kaposi’s sarcoma Lymphoma M. tuberculosis infection Cryptococcosis Normal radiograph Upper respiratory infection Bronchiolitis P. jirovecii infection Retinal necrosis Hemorrhage FIGURE 155-1. Cytomegalovirus retinitis. “Pizza pie” or “cheese and ketchup” appearance is demonstrated by hemorrhages and the dirty white granular-appearing retinal necrosis adjacent to major vessels. [Photograph contributed by Richard E. Wyszynski, MD. Reproduced with permission from Knoop KJ, Stack LB, Storrow AB, Thurman RJ: The Atlas of Emergency Medicine , 3rd ed, © 2009 by McGraw-Hill, Inc., New York.] Tintinalli_Sec13_p0997-1100.indd 1038 8/2/19 8:12 PM

ar-appearing retinal necrosis adjacent to major vessels. [Photograph contributed by Richard E. Wyszynski, MD. Reproduced with permission from Knoop KJ, Stack LB, Storrow AB, Thurman RJ: The Atlas of Emergency Medicine , 3rd ed, © 2009 by McGraw-Hill, Inc., New York.] Tintinalli_Sec13_p0997-1100.indd 1038 8/2/19 8:12 PM CHAPTER 155: Human Immunodeficiency Virus Infection 1039  PNEUMOCYSTIS PNEUMONIA PCP is the most common opportunistic infection among AIDS patients.27 The causal agent is known as P . jirovecii (previously known as P . carinii), previously classified as a protozoan but now reclassified as a fungus. Approximately 70% of HIV-infected patients acquire PCP at some time during their illness, and PCP is often the initial opportunistic infection that establishes the diagnosis of AIDS. This infection is the most frequent serious complication of HIV infection in the United States and the most common identifiable cause of death in patients with AIDS. The incidence of PCP has decreased among patients on ART but remains a high trigger for morbidity and mortality. 28 PCP pneumonia typically occurs in patients with a low CD4 count of <200 cells/mm3. The classic presenting symptoms of PCP are fever, cough (typically nonproductive), and shortness of breath (progressing from being present only with exertion to being present at rest). Symptoms are often insidious and accompanied by fatigue. Chest radiographs most often show diffuse interstitial infiltrates (Table 155-3), but negative radiographic findings exist in 15% to 25% of patients with PCP . 29 The lactate dehydrogenase level may be elevated in patients with PCP , but this test has low sensitivity and specificity, impairing utility. Arterial blood gas analysis usually demonstrates hypoxemia and an increase in the alveolar-arterial gradient. Suspect early PCP if a patient demonstrates a decrease in pulse oximetric values with exercise; even an ED “walk” can detect this exercise desaturation. Presumptive diagnosis of PCP is possible in the ED if there is hypoxemia without any other explanation. Inpatient diagnostics include bronchoscopy with specimen analyses. The preferred therapy is trimethoprim-sulfamethoxazole (Table 155-2). 30-32 Use body mass–based dosing, 15 to 20 milligrams/kg/d PO or IV; a typical PO dose is two double-strength tablets three times daily for 21 days. For moderate to severe disease, use IV trimethoprim-sulfamethoxazole (15 to 20 milligrams/kg of trimethoprim and 75 to 100 milligrams/kg of sul famethoxazole per day). Adverse reactions, including rash, fever, and neutropenia, occur in up to 65% of AIDS patients. Alternative regimens include trimethoprim-dapsone, clindamycin-primaquine, or atovaquone. Pentamidine is an alternative IV agent (Table 155-2). Add systemic steroids in patients with a partial pressure of arterial oxygen of <70 mm Hg or an alveolar-arterial gradient of >35 mm Hg. Oral prednisone, starting at 40 milligrams twice daily and tapering over 21 days (Table 155-2), is a common approach. 33 Start ART or continue any existing regimen. Seventy percent of patients have reinfection within 18 months, which is why prophylactic therapy is key. Oral trimethoprim-sulfamethoxazole, one double-strength tablet daily, is preferred. Prophylaxis for all patients with CD4+ T-cell counts of <200 cells/mm 3 is another common approach to mitigate PCP . Repeat PCP infections are often less responsive to therapy.  TUBERCULOSIS Clinical manifestations of tuberculosis in HIV-infected patients vary according to the severity of immunosuppression. Typical presentations of tuberculosis occur in patients with CD4+ T-cell counts of >200 to 500 cells/mm 3.

ch to mitigate PCP . Repeat PCP infections are often less responsive to therapy.  TUBERCULOSIS Clinical manifestations of tuberculosis in HIV-infected patients vary according to the severity of immunosuppression. Typical presentations of tuberculosis occur in patients with CD4+ T-cell counts of >200 to 500 cells/mm 3. Those with tuberculosis and advanced HIV infection, with CD4 cell counts <100 cells/mm3, often have extrapulmonary or disseminated disease.34,35 Classic manifestations include cough with hemoptysis, night sweats, prolonged fevers, weight loss, and anorexia. With worsening immunosuppression, patient presentation becomes less classic; in addi tion, upper lobe involvement and cavitary lesions are less common as patients become more immunosuppressed, particularly among patients with late-stage AIDS. 36 Negative purified protein derivative skin tuberculosis test results are frequent among AIDS patients due to immunosup pression. Definitive diagnosis of tuberculosis usually occurs with stain and culture of expectorated sputum, although some cases require bronchoscopy. Later stage HIV is also associated with increased frequency of extrapulmonary tuberculosis with clinical manifestation associated with the involved sites of infection. Frequent sites of dissemination are peripheral lymph nodes, bone marrow, CNS, GI system, and urogenital system. In the ED, think of tuberculosis in any HIV-infected patients with pulmonary symptoms, and begin precautions to avoid transmission. Place the patient in an isolation room and with an appropriate mask immediately and until the diagnosis is excluded. Current treatment guidelines recommend a four-drug initial empirical therapy to include a combination of isoniazid, rifampin, ethambutol, and pyrazinamide (Table 155-2; see Chapter 67, “Tuberculosis”). 37-39 Multidrug-resistant tuberculosis remains a concern, increasing the need for suspicion and early isolation. All HIV-infected patients with positive purified protein derivative skin tests should receive isoniazid plus pyridoxine for 9 to 12 months; alternatives include rifampin or rifabutin for 4 months. In addition, give empiric treatment to HIV-infected persons in close con tact with another patient with active tuberculosis. Start ART or continue a regimen, regardless of CD4 count.  OTHER PNEUMONIAS Bacterial pneumonia is the most common pulmonary infection in HIVinfected patients. Morbidity and mortality are high, with an inpatient mortality rate of 10%. 41 Common pathogens are S. pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Productive cough, leukocytosis, and the presence of a focal infiltrate suggest bacterial pneumonia. Risk factors and prognosis for bacterial pneumonia among HIV-infected persons on newer ART are similar to those of the general population. Patients with severe immunosuppression are predisposed to dis seminated fungal infections such as those caused by C. neoformans, H. capsulatum, and Aspergillus fumigatus. Cytomegalovirus or M. avium complex infections can occur in patients with extremely low CD4 cell counts (<50 cells/mm 3).  NONINFECTIOUS PULMONARY DISORDERS Lymphocytic interstitial pneumonia may present with dyspnea and hypoxia. Typical radiographic findings include ground-glass opacities and/or nodules. Treat lymphocytic interstitial pneumonia with a sys temic antiretroviral regimen. Chronic obstructive pulmonary disease and asthma are seen with increasing frequency and are managed with traditional therapies. 43 HIV-infected persons are at increased risk for lung cancer, which may include Kaposi’s sarcoma and lymphoma.44,45 Increased incidence of pulmonary hypertension may be related to HIV infection, injecting drug use, and/or ART.

se and asthma are seen with increasing frequency and are managed with traditional therapies. 43 HIV-infected persons are at increased risk for lung cancer, which may include Kaposi’s sarcoma and lymphoma.44,45 Increased incidence of pulmonary hypertension may be related to HIV infection, injecting drug use, and/or ART. 46 Pulmonary hypertension may present with dyspnea, cough, or chest pain and should be treated with ART. CARDIOVASCULAR COMPLICATIONS Cardiovascular disease is one of the most common causes of death. 47 HIV-infected individuals are at increased risk of cardiovascular disease.48-51 Cardiovascular complications may be related to opportunistic infections, structural defects, or drug toxicity. HIV-associated cardiovascular conditions include ischemic heart disease, cardiomyopathy, infective endocarditis, pericardial effusion, congestive heart failure, or dysrhythmias. Cardiotoxicity may result from illicit substances, such as cocaine and methamphetamine, or therapeutic agents, such as pentamidine and zidovudine. RENAL COMPLICATIONS Monitor renal function during care for those with HIV infection, because renal insufficiency secondary to HIV-associated nephropathy, HIV immune complex disease, prerenal azotemia, drug nephrotoxicity, and arterionephrosclerosis are possible. 52,53 Risk factors for HIV-associated nephropathy include African descent, low CD4 count, and high viral load. 54 Nephrotoxicity may rise from ART, including agents such as atazanavir, tenofovir, acyclovir, foscarnet, indinavir (associated with nephrolithiasis), trimethoprim, and other agents. In the ED, check serum creatinine, estimated glomerular filtration rate, and urinary sediment. Many medications, including antiretroviral agents, have renal metabolism and require dosage adjustment for patients with renal insufficiency. GI COMPLICATIONS GI disorders compose some of the most common complaints in patients with HIV . Frequent presenting symptoms include odynophagia, abdominal pain, and diarrhea. ED evaluation seeks to identify the severity of symptoms and perform appropriate initial diagnostic studies. Therapy starts with volume and electrolyte repletion, with antimicrobial therapy Tintinalli_Sec13_p0997-1100.indd 1039 8/2/19 8:12 PM

equent presenting symptoms include odynophagia, abdominal pain, and diarrhea. ED evaluation seeks to identify the severity of symptoms and perform appropriate initial diagnostic studies. Therapy starts with volume and electrolyte repletion, with antimicrobial therapy Tintinalli_Sec13_p0997-1100.indd 1039 8/2/19 8:12 PM 1040 SECTION 13: Infectious Diseases when appropriate. Disposition is based on degree of immunosuppres sion, the duration of symptoms, the clinical appearance of the patient, and the response to ED therapy.  ORAL AND ESOPHAGEAL COMPLICATIONS Oral Candidiasis/Thrush Oral lesions are common in HIV-infected patients, frequently contributing to malnutrition. The appearance of oral lesions in HIV patients serves as a potential clinical marker for degree of immunodeficiency, with increased rates of thrush occurring with CD4 counts of <500 cells/mm 3. Oral candidiasis (“thrush”; Figure 155-2) affects >80% of AIDS patients. The tongue and buccal mucosa are commonly involved, and the plaques are easily scraped from the erythematous base. Differentiation from hairy leukoplakia (adherent, white, thickened lesion[s] on the lateral tongue border) is challenging, but microscopic examination of a potassium hydroxide smear can confirm the diagnosis. Oral fluconazole, 100 mg once daily for 7 to 14 days, is first-line treatment; clotrimazole and nystatin are second-line treatments. Other Oral Lesions Other causes of painful oral and perioral lesions include hairy leukoplakia, which is associated with the Epstein-Barr virus, leads to epithelial thickening on the lateral borders of the tongue, and is adherent. Herpes simplex virus infection usually has painful oral and perioral vesicular lesions, with diagnosis confirmed by identifica tion of multinucleated giant cells in scrapings or by culture. Both herpes simplex virus infection and hairy leukoplakia are responsive to oral acyclovir. Oral Kaposi’s sarcoma appears as a nontender, well-circumscribed, slightly raised violaceous lesion. Diagnosis requires biopsy, with topical treatments being palliative and started outside the ED. Esophageal involvement may occur with Candida, herpes simplex virus, and cytomegalovirus infection. Complaints of odynophagia, dysphagia, or chest pain may be indicative of esophagitis and be debilitating. In those with CD4+ T-cell counts of <200 cells/mm 3, Candida is responsible for the majority of bouts. Treatment for esophagitis is presumptive in the ED with oral fluconazole (Table 155-2). IV amphotericin B is a second-line therapy and used when oral treatment fails. Endoscopy, histologic staining and culture of lesions, and biopsy should be done for patients who fail to respond to therapy or have atypical presentations. Cytomegalovirus and herpes simplex virus infections discovered by endoscopy are treated with ganciclovir and acyclovir, respectively.  DIARRHEA Diarrhea is the most frequent GI complaint of patients with HIV . Infectious causes include bacteria (Shigella , Salmonella, enteroadher ent Escherichia coli, Entamoeba histolytica, Campylobacter, M. aviumintracellulare complex, Clostridium difficile, and others), parasites (Giardia lamblia , Cryptosporidium, Cystoisospora belli [previously Isospora belli], and others), viruses (cytomegalovirus, herpes simplex virus, HIV , and others), and fungi ( H. capsulatum, C. neoformans, and others). In those with CD4 <200 cells/mm 3, consider Cryptosporidium and microsporidia; if CD4 is <50 cells/mm 3, patients are at risk for cytomegalovirus and MAC. Sexual transmission of shigellosis and lymphogranuloma venereum is increasing and may contribute to etiology of diarrhea in men who have sex with men. In many cases, a pathogen is never identified.

3, consider Cryptosporidium and microsporidia; if CD4 is <50 cells/mm 3, patients are at risk for cytomegalovirus and MAC. Sexual transmission of shigellosis and lymphogranuloma venereum is increasing and may contribute to etiology of diarrhea in men who have sex with men. In many cases, a pathogen is never identified. In the ED, exclude dietary causes and medication effects first; then, obtain stool culture for enteric bacteria, a specimen for C. difficile toxin (in the setting of antibiotic use), and multiple stool specimens for ova and parasite examination (including acid-fast bacilli and trichrome stain). Bacterial infections generally follow a more acute and fulminant course, whereas parasitic infections are frequently indolent. If suspect ing bacterial infection in a patient with CD4 count <200 cells/mm 3 and clinically severe diarrhea (six or more episodes or bloody stools and/ or fevers/chills), start empiric treatment with ciprofloxacin by mouth. Cryptosporidium and Cystoisospora infections are common parasitic causes associated with profuse watery diarrhea; both are detected by modified acid-fast staining of a stool specimen. Cystoisospora infection is usually responsive to trimethoprim-sulfamethoxazole, but relapse is common. Cryptosporidiosis is difficult to treat; ART is the mainstay of treatment, coupled with supportive care, including rehydration and electrolyte repletion. The efficacy of paromomycin and nitazoxanide and other agents is unclear. In patients with CD4 <50 cells/mm 3, the most common diarrheal pathogens are cytomegalovirus and M. avium-intracellulare complex, each requiring biopsy for diagnosis. Use prolonged antimicrobial ther apy; relapse is frequent for both infections. About 15% of patients with late-stage AIDS experience severe, highvolume watery diarrhea absent a clear pathogen, with the presumed diagnosis of AIDS-related enteropathy. Octreotide may aid some of these patients. Crofelemer may reduce symptoms of noninfectious diarrhea in patients with HIV . 56 Diarrhea can also be a side effect of protease inhibitors; non-Hodgkin’s lymphoma and Kaposi’s sarcoma can also present with diarrhea if GI tract involvement is present. Pancreatic insufficiency may represent a treatable cause of chronic diarrhea. ED management consists of repletion of fluid and electrolytes and treatment of targeted pathogens, as noted earlier; admit those with sus pected bacteremia, AIDS, significant dehydration, malnutrition, or electrolyte imbalance. Patients who appear nontoxic and can tolerate liquids are eligible for outpatient care and follow-up to obtain test results. In the absence of bloody diarrhea or systemic complaints, treat patients symptomatically with antimotility agents (e.g., loperamide, diphenoxylate).  OTHER GI COMPLICATIONS Coinfection with hepatitis B virus and hepatitis C virus is common, especially among injection drug users. Opportunistic infection with cytomegalovirus, Cryptosporidium, M. avium-intracellulare complex, and M. tuberculosis also may cause hepatitis. Cryptosporidium may also cause cholangiopathy. Drug-related hepatitis and hypersensitivity are other possibilities. Anorectal disease is common in AIDS patients. Proctitis presents with painful defecation, rectal discharge, or tenesmus. Common causative organisms include Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, lymphogranuloma venereum, and herpes simplex virus. Proctocolitis includes the same symptoms plus diarrhea, and multiple bacterial organisms may be responsible (most commonly Shigella, Campylobacter, and E. histolytica ). Evaluation includes anos copy with microscopic examination, Gram staining, and culture of pus and/or stool.

nuloma venereum, and herpes simplex virus. Proctocolitis includes the same symptoms plus diarrhea, and multiple bacterial organisms may be responsible (most commonly Shigella, Campylobacter, and E. histolytica ). Evaluation includes anos copy with microscopic examination, Gram staining, and culture of pus and/or stool. CUTANEOUS COMPLICATIONS Noninfectious cutaneous disorders are common in HIV and can include xerosis, eczema, seborrheic dermatitis, psoriasis, and drug reactions. Pruritus is common, and ED evaluation includes history, physical examination, removal of offending agents, and treatment of the underlying condition. Symptomatic treatment with emollients and antipruritic agents can be effective. FIGURE 155-2. Oral candidiasis (thrush). Extensive thrush is seen on the hard and soft palate of this immunocompromised patient. [Photograph contributed by Lawrence B. Stack. Reproduced with permission from Knoop KJ, Stack LB, Storrow AB, Thurman RJ: The Atlas of Emergency Medicine, 3rd ed, © 2009, McGraw-Hill, Inc., New York.] Tintinalli_Sec13_p0997-1100.indd 1040 8/2/19 8:12 PM

een on the hard and soft palate of this immunocompromised patient. [Photograph contributed by Lawrence B. Stack. Reproduced with permission from Knoop KJ, Stack LB, Storrow AB, Thurman RJ: The Atlas of Emergency Medicine, 3rd ed, © 2009, McGraw-Hill, Inc., New York.] Tintinalli_Sec13_p0997-1100.indd 1040 8/2/19 8:12 PM CHAPTER 155: Human Immunodeficiency Virus Infection 1041  CUTANEOUS INFECTIONS Skin and soft tissue infections occur in the HIV-infected population, and often are signs of disseminated disease or bacteremia. Methicillin-resistant S. aureus colonization and infection are prevalent and are associated with low CD4+ cell counts, men who have sex with men, anal intercourse, previous methicillin-resistant S. aureus infections, and illicit drug use. 59,60 Human papillomavirus infections manifesting as condyloma acuminata or warts are common; treatment is cosmetic or symptomatic and includes cryotherapy, topical therapy, or laser therapy. Intertriginous infections with Candida or Trichophyton are frequent in HIV-positive patients. Treatment is with topical clotrimazole, miconazole, or ketoconazole. Molluscum contagiosum presents as CD4 counts decrease to <100 cells/mm with pearly flesh-colored papules with central umbilication; the goal of localized treatment is primarily cosmetic. Scabies occurs in about 20% of HIV-infected patients, with scaly, persistent pruritic eruptions. Treat with permethrin 5% cream or oral ivermectin. Atypical presentations, such as papular or crusted scabies, may also occur. Cutaneous cytomegalovirus, tuberculosis, syphilis, coccidioidomycosis, histoplasmosis, and cryptococcosis are other considerations and may mandate systemic treatment.  HERPES SIMPLEX VIRUS Herpes simplex virus infections are common and either localized or systemic. In patients with immunosuppression, infection may become progressive and chronic (see Chapter 153, “Sexually Transmitted Infections”). IV acyclovir is the therapy for extensive disease (Table 155-2).  VARICELLA-ZOSTER VIRUS INFECTION Reactivation of varicella-zoster virus is more common in patients with HIV infection and AIDS than in the general population. The clinical course is prolonged, and complications are more frequent. In HIV-positive patients, oral acyclovir, famciclovir, and valacyclovir are options for treatment for those with limited involvement in absence of significant immunosuppression (Table 155-2). Patients with dissemi nated disease or ophthalmic involvement should receive IV acyclovir.  KAPOSI’S SARCOMA Kaposi’s sarcoma appears more often in men who have sex with men than in other risk groups. Clinically, it consists of firm, painless, raised, brown-black or purple patches, plaques, or nodules (see Figure 251-30). Common sites are the face, chest, genitals, and oral cavity, but widespread dissemination involving internal organs may occur. Biopsy con firms the diagnosis. Radiotherapy treats localized disease; widespread disease may be responsive to chemotherapy in combination with ART.  BACILLARY ANGIOMATOSIS In patients with CD4 count <100 cells/mm3, Bartonella may cause vascular proliferations of the skin, although any organ may be involved. Firm, red or violaceous nodules are painful and may resemble pyogenic granulomas or Kaposi’s sarcoma. Treatment typically consists of doxycycline or erythromycin, and patients should be referred for biopsy. SEXUALLY TRANSMITTED INFECTIONS Sexually transmitted infections, HIV , and viral hepatitis share common routes of transmission and may coexist. 62-64 Genital ulcers caused by diseases such as herpes, chancroid, and syphilis are portals of entry for HIV . There is more frequent HIV seropositivity in patients with genital ulcers, gonorrhea, and chlamydial infections.

itted infections, HIV , and viral hepatitis share common routes of transmission and may coexist. 62-64 Genital ulcers caused by diseases such as herpes, chancroid, and syphilis are portals of entry for HIV . There is more frequent HIV seropositivity in patients with genital ulcers, gonorrhea, and chlamydial infections. The prevalence of sexually transmitted infections, including syphilis, is increasing and warrants enhanced surveillance. 65 See Chapter 153 for details. IMMUNIZATION OF HIV-INFECTED PATIENTS HIV-infected persons should not receive live-virus or live-bacteria vac cines.66 The exception to this rule is the measles-mumps-rubella vaccine. Killed or inactivated vaccines pose no danger to immunosuppressed patients.67 Because symptomatic HIV-infected persons have a subopti mal response to vaccines, all single-dose vaccines are best given early in the course of HIV infection. Table 155-4 summarizes recommendations for common immunizations. ANTIRETROVIRAL THERAPY After the introduction of ART, sharp declines in AIDS incidence and mortality occurred, transforming HIV therapeutics into long-term management of a chronic infection. General therapeutic goals include: (1) prolonging and improving the quality of life; (2) reducing viral load as much as possible to halt disease progression and prevent or reduce the development of resistant variants; (3) promoting immune reconstitution, both quantitative (CD4+ T-cell count) and qualitative (pathogen-specific immune response); and (4) reducing side effects and maintaining therapeutic options. A complete drug list and up-to-date guide for the general classes of antiretroviral drugs, principles for initiating therapy, and common adverse reactions are on the Centers for Disease Control and Prevention website (https://www.cdc.gov/hiv/guidelines/index.html). The five main classes of antiretroviral drugs are (1) nucleoside reverse transcriptase inhibitors, which interfere with the action of reverse tran scriptase (e.g., zidovudine); (2) nonnucleoside reverse transcriptase inhibitors, which bind to reverse transcriptase and block RNA- and DNA-dependent DNA polymerase activity (e.g., efavirenz); (3) protease inhibitors, which block HIV protease, a key enzyme in establishing HIV infectivity (e.g., indinavir); (4) entry inhibitors, which prevent HIV entry into cells by targeting specific viral surface proteins or their corresponding receptors (e.g., enfuvirtide); and (5) integrase inhibitors, which work by blocking integrase, a protein that HIV needs to insert its viral genetic material into the genetic material of an infected cell (e.g., raltegravir). Preferred initial treatment regimens include at least three drugs—two nucleoside reverse transcriptase inhibitors plus one of the following classes: nonnucleoside reverse transcriptase inhibitor, protease inhibitor (boosted with ritonavir), or integrase strand transfer inhibitor. The newest guidelines recommend that all HIV-infected patients, regardless of CD4+ cell count, start ART in order to reduce morbidity and mortality associated with HIV infection and to prevent HIV transmission. 68 Education and counseling are considered an integral part of ART initiation regarding risk and benefits as well as developing strategies to optimize adherence. 69 For these reasons, decisions regarding initiation of and changes in ART should be made in consultation with the primary care physician and an infectious disease consultant. DRUG INTERACTIONS AND ADVERSE EFFECTS IN HIV-INFECTED PATIENTS Current ART programs include a standard three-drug regimen that may cause a range of changes in metabolic or physiologic functions and be toxic.

nges in ART should be made in consultation with the primary care physician and an infectious disease consultant. DRUG INTERACTIONS AND ADVERSE EFFECTS IN HIV-INFECTED PATIENTS Current ART programs include a standard three-drug regimen that may cause a range of changes in metabolic or physiologic functions and be toxic. Table 155-5 shows the currently available antiretroviral TABLE 155-4 Immunization Recommendations for Adult Human Immunodeficiency Virus–Infected Patients Recommended Vaccines Recommendation Tetanus, diphtheria, and pertussis (Tdap) One booster in adulthood Tetanus-diphtheria toxoid (Td) Every 10 y Pneumococcal One dose Influenza (inactivated) One dose annually Hepatitis B Three doses over a 2-y period Withhold in Severe Immunodeficiency Measles-mumps-rubella Avoid in patients with CD4+ T-cell count <200 cells/mm3 Varicella Avoid in patients with CD4+ T-cell count <200 cells/mm3 Contraindicated Vaccines Oral polio vaccine Smallpox vaccine Live attenuated influenza vaccine Tintinalli_Sec13_p0997-1100.indd 1041 8/2/19 8:12 PM 1042 SECTION 13: Infectious Diseases (Continued) TABLE 155-5 Antiretroviral Medications, Major Adverse Effects, and Interacting Drug Effects 70 (Continued) Antiretroviral Medications* Adverse Effects Interacting Drugs Effects of Interaction Nucleoside reverse transcriptase inhibitors Abacavir Stevens-Johnson syndrome, hypersensitivity reaction Didanosine Peripheral neuropathy, lactic acidosis, pancreatitis, retinal changes, insulin resistance/diabetes mellitus Emtricitabine Skin hyperpigmentation/discoloration, acute exacerbation of hepatitis may occur in HBV/HCV patients who discontinue drug Lamivudine Acute exacerbation of hepatitis may occur in HBV/HCV patients who discontinue drug Stavudine Pancreatitis, lactic acidosis/hepatic steatosis (rare), peripheral neuropathy, ascending muscle weakness (rare), dyslipidemia, lipoatrophy Tenofovir Pancreatitis, headache, renal insufficiency, diarrhea, nausea, vomiting, osteomalacia, acute exacerbation of hepatitis may occur in HBV/HCV patients who discontinue drug Zidovudine Bone marrow suppression, nausea, vomiting, headache, lactic acidosis/hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, lipoatrophy, myopathy

Tenofovir Pancreatitis, headache, renal insufficiency, diarrhea, nausea, vomiting, osteomalacia, acute exacerbation of hepatitis may occur in HBV/HCV patients who discontinue drug Zidovudine Bone marrow suppression, nausea, vomiting, headache, lactic acidosis/hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, lipoatrophy, myopathy Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Anticonvulsants, rifampin Anticonvulsants: decreased concentration of antiretrovirals (some contraindicated), rifampin: decreased NNRTI (contraindicated with some NNRTIs) Delavirdine Transaminitis, rash, headache Efavirenz Depression, psychosis, suicidal ideation, rash, serum transaminase elevation, hyperlipidemia, QT prolongation Midazolam Increased concentration of midazolam (oral administration contraindicated) Etravirine Rash (including Stevens-Johnson syndrome, hypersensitivity reaction), nausea

ansaminitis, rash, headache Efavirenz Depression, psychosis, suicidal ideation, rash, serum transaminase elevation, hyperlipidemia, QT prolongation Midazolam Increased concentration of midazolam (oral administration contraindicated) Etravirine Rash (including Stevens-Johnson syndrome, hypersensitivity reaction), nausea Nevirapine Rash (including Stevens-Johnson syndrome), hepatic failure Rilpivirine Rash, depression, insomnia, headache, hepatoxicity, QT prolongation Proton pump inhibitors Decreased concentration of antiretroviral (contraindicated) Protease inhibitors Hyperlipidemia, hyperglycemia, fat maldistribution Antiarrhythmics, anticonvulsants, anticoagulants and antiplatelet agents, midazolam, rifampin, HMG-CoA reductase inhibitors Antiarrhythmics: increased levels of both drugs (some contraindicated); anticonvulsants: decreased concentration of antiretroviral and varying concentration of the interacting drug (some contraindicated); anticoagulants: varying impact on anticoagulant concentration (monitoring needed with warfarin, coadministration not recommended with others); midazolam: increased midazolam (do not administer orally); rifampin: decreased concentration of antiretroviral (contraindicated); HMG-CoA reductase inhibitors: increased risk of rhabdomyolysis Amprenavir Toxicity from propylene glycol diluent Atazanavir Indirect hyperbilirubinemia, prolonged PR interval, cholelithiasis, nephrolithiasis, renal insufficiency, serum transaminase elevations, rash Antacids, H 2-receptor antagonists, proton pump inhibitors Decreased absorption of atazanavir; space use of antacids/H 2-receptor antagonists; proton pump inhibitors contraindicated in some situations Diltiazem Increased concentration of diltiazem (decrease diltiazem dose by half) Darunavir Headache, nausea, diarrhea, rash (including Stevens-Johnson syndrome, toxic epidermal necrolysis, etc.), hepatotoxicity, serum transaminase elevation, increase in serum creatinine Fosamprenavir Rash, diarrhea, nausea, vomiting, headache, serum transaminase elevation, possible increased bleeding episodes in patients with hemophilia, nephrolithiasis Indinavir Nephrolithiasis, nausea, hepatitis, nephrotoxicity, indirect hyperbilirubinemia, headache, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, hemolytic anemia, possible increased bleeding episodes in patients with hemophilia

Fosamprenavir Rash, diarrhea, nausea, vomiting, headache, serum transaminase elevation, possible increased bleeding episodes in patients with hemophilia, nephrolithiasis Indinavir Nephrolithiasis, nausea, hepatitis, nephrotoxicity, indirect hyperbilirubinemia, headache, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, hemolytic anemia, possible increased bleeding episodes in patients with hemophilia Nelfinavir Secretory diarrhea, possible increased bleeding episodes in patients with hemophilia, serum transaminase elevation Tintinalli_Sec13_p0997-1100.indd 1042 8/2/19 8:12 PM