Human Immunodeficiency Virus

The appearance of the human immunodeficiency virus (HIV) approximately two decades ago has changed the face of medicine. HIV infected patients are at risk for opportunistic infections and many require additional prophylactic antimicrobial therapy. Each year numerous developments in the management of HIV infection, primarily new medications, are introduced. In 1986 zidovudine was the first antiretroviral approved for the treatment of HIV infection. Today 16 antiretroviral drugs are currently available. Patients infected with HIV are treated with complex regimens of antiretroviral "cocktails" including reverse transcriptase inhibitors, protease inhibitors, and nonnucleoside reverse transcriptase inhibitors. Each medication has numerous side effects, some of which are lethal. This chapter reviews the common problems faced by emergency physicians when treating HIV infected patients, opportunistic infections and reactions to highly active antiretroviral therapy (HAART).

Opportunistic Infections

• The precise opportunistic infection (OI) any given patient will develop depends upon the level of immunosuppression and the types of exposures the patient experiences.

Pneumocystis carinii Pneumonia (PCP)

• P. carinii is an organism of low virulence in the immunocompetent host and is found in the lungs of both humans and animals worldwide.
• PCP continues to be a common OI in North America and is a common presentation in those newly diagnosed with HIV infection. Despite prophylaxis with trimethoprim/ sulfamethoxazole and the ensuing reduction in the incidence of PCP, this infection remains a substantial cause of morbidity and mortality.

Clinical Presentation

• PCP is an interstitial pneumonia with an insidious onset of shortness of breath, dry cough, and fever that develops over weeks to months, usually in HIV infected patients with CD4 count <200.
• Tachypnea and tachycardia are common findings, and auscultation of the lungs reveals crackles in approximately one-third of infected adults. Hypoxemia and an elevated arterial-alveolar gradient may be noted and are reflections of the severity of disease.
• The chest radiograph classically shows bilateral diffuse interstitial infiltrates. Unilateral infiltrates, cavities, pneumatoceles, lymphadenopathy, effusions and normal appearances on chest radiograph are atypical, but do occur.
• Serum lactic dehydrogenase (LDH) may also be elevated but is nonspecific.
• P. carinii is rarely found in expectorated sputum but may be detected by inducing sputum with inhaled saline. Fiberoptic bronchoscopy has the highest yield of >90%.

ED Management

• Many patients with mild to moderate disease are treated empirically based on clinical diagnosis.
• Trimethoprim/sulfamethoxazole remains the drug of choice and may be administered either orally or intravenously. The dose is 15-20 mg/kg/day trimethoprim and 75-100 mg/kg/day sulfamethoxazole in 3 or 4 divided doses. Clindamycin (900 mg IV q 8 h) plus primaquine (30 mg po q day) is an alternative therapy for patients who are allergic to sulfa medications. Other alternatives include atovaqone (750 mg po BID), pentamidine (4 mg/kg/d IV).
• Prednisone is indicated for patients who are hypoxic (pO2 < 70 mm Hg) and should be administered 15-30 min before the antibiotics are given. The dose is 40 mg po BID for 5 days, then 40 mg po q day for 5 days, and then 20 mg po q day for 11 days.

Toxoplasmosis

• Taxoplasma gondii is a coccidian parasite that infects animals and humans worldwide. Infection in immunocompetent individuals is rarely of clinical significance, but in immunocompromised patients infection commonly involves the brain, lungs, and eyes.
• Encephalitis is the most common presentation, and it may demonstrate a wide array of clinical manifestations including altered mental status, weakness, sensory abnormalities, meningismus, cerebellar signs, movement disorders, seizures, and neuropsychiatric disturbances.
• Presumptive diagnosis is made by detecting multiple bilateral cerebral lesions on computer tomography of the brain. The lesions are "ring-enhancing", or contrast enhancing in up to 80% of patients. A single lesion may be seen with Toxoplasma encephalitis in up to 40% of patients, but the suspicion for central nervous system (CNS) lymphoma is elevated with this finding.
• These patients should be admitted and treated with oral pyramethamine, folinic acid and either sulfadiazine or clindamycin for 2 wk.
• Maintenance therapy is required for life due to a relapse rate of 80%.

Cytomegalovirus (CMV)

• Retinitis is the most common manifestation of CMV disease and usually occurs when the patient�s CD4 cell count is < 50 cells/mm3. CMV also causes esophagitis, enteritis, colitis, and pneumonia.
• The symptoms of CMV retinitis are nonspecific and include floaters, flashing lights, loss of visual field, or a vague sense of visual loss. Visual impairment caused by focal necrotizing retinitis can rapidly progress to blindness.
• The presumptive diagnosis is made by observing white fluffy retinal infiltrates occurring within areas of hemorrhage on fundoscopic exam.
• Treatment with intravenous gancyclovir or foscarnet is usually empiric due to the invasive nature of obtaining retinal or vitreous material for examination.

Cryptococcus

• Cryptococcus neoformans is a ubiquitous encapsulated organism.
• Cryptococcus fungus causes subacute meningitis, as well as pneumonia and skin lesions, in patients with T-cell defects. AIDS is the predisposing factor in approximately 90% of cases.
• The presenting symptoms of crytococcal meningitis are mild and nonspecific, such as nausea, headache, dizziness, irritability, somnolence, or confusion. Cranial nerve dysfunction and papilledema are noted in up to 20% and 30%, respectively. Seizures occur late in the course of infection. Fever is not always present and neurologic examination is often normal. Most patients have minimal or no nuchal rigidity.
• Diagnosis is made by identifying the yeast in the cerebrospinal fluid (CSF) with an India ink preparation, by cryptococcal antigen detection, or by culture. Over 90% of patients will test positive for serum cryptococcal antigen. The opening pressure of the CSF during lumbar puncture is often elevated, and the CSF glucose is decreased. Usually more than 20 white blood cells are noted. A normal CSF profile in the setting of suspected cryptococcal meningitis mandates fungal culture of the CSF.
• Routine laboratory testing, i.e., CBC and sedimentation rate, are usually normal.
• The treatment of choice is intravenous amphotericin B (0.5 0.8 mg/kg/d IV) plus 5 FC (25 mg/kg po q 6 h) for 2 wk or until the patient is clinically stable is. Oral fluconazole is required for lifelong suppressive therapy.

Suggested Reading

• USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1999
• USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. Clin Infect Dis 2000; 30:S29-65.

Table: Adverse reactions of nucleoside reverse transcriptase inhibitors
Zidovudine (AZT, Retrovir) headache nausea bone marrow suppression myopathy	Didanosine (ddI, Videx) diarrhea peripheral neuropathy pancreatitis elevation of ALT/AST	Zalcitabine (ddC) peripheral neuropathy stomatitis rash
Stavudine (d4T,Zerit) peripheral neuropathy gastrointestinal upset headache elevated ALT/AST	Lamivudine (3TC, Epivir) nausea headache fatigue insomnia	Abacavir (Zigen) hypersensitivity reaction nausea/vomiting/ diarrhea severe rash fever
Warrants discontinuation of all antiretrovirals

Highly Active Antiretroviral Therapy (HAART)

• The widespread use of combination therapy with multiple antiretroviral agents has reduced the morbidity and mortality due to HIV infection. Death rates due to HIV have declined as much as 65% in the United States. Despite these optimistic results, only one-half of patients achieve maximal viral suppression. Many factors prevent successful treatment including viral resistance, inadequate adsorption due to gastrointestinal disease, lack of adherence to complex drug regimens, adverse drug effects, expense, and coincident mental health and substance abuse problems.
• Emergency physicians should never discontinue HAART unless potentially lethal adverse effects develop. If this situation occurs, then all antiretrovirals should be stopped simultaneously to prevent the development of resistance.
• Many new antiretroviral agents are currently under development and emergency physicians must continue to be vigilant and prepare for the recognition and management of adverse effects.

Nucleoside Reverse Transcriptase Inhibitors

• The first class of antiretrovirals to be introduced was the nucleoside reverse transcriptase inhibitors (NRTIs). There are currently six NRTI�s available and although their mechanism of action is similar, adverse reactions for each agent are unique.
• Common symptoms include fever, rash, and gastrointestinal complaints. Over 85% of cases began within the first 6 wk of therapy. A rare but deadly adverse reaction is lactic acidosis with severe hepatomegaly. Other common adverse reactions are listed in table.
• Adefovir dipiroxil is a novel nucleotide reverse transcriptase inhibitor. Renal toxicity is the most important adverse effect and is seen in over one-third of patients. Adefovir should be discontinued if renal function is impaired.

Nonnucleoside Reverse Transcriptase Inhibitors

• All NNRTIs are capable of causing a rash that may be mild and self-limited or severe and capable of progressing to Stevens-Johnson syndrome. Mild rashes are treated with oral antihistamines or topical steroid creams. Antiretrovirals may be continued and the patient promptly reevaluated by their primary physician. However, if the rash is severe or associated with fever, severe pruritis, ulcers, blisters, vomiting, diarrhea, mucosal involvement, or muscle or joint pain, then all antiretrovirals must be discontinued.
• Common adverse reactions of the NNRTIs are listed in (Table 11.8).

Table: Adverse reactions of non-nucleoside reverse transcriptase inhibitors
Nevirapine (Viramune) Stevens-Johnson syndrome severe rash fever elevated ALT/AST headache	Delavirdine (Rescriptor) severe rash diarrhea fatigue headache	Efavirenz (Sustiva) CNS effects severe rash elevated ALT/ALT
Warrants discontinuation of all antiretrovirals

Table: Adverse effects of protease inhibitors
Saquinovir (Invirase) gastrointestinal symptoms elevated ALT/AST	Indinavir (Crixivan) nephrolithiasis hyperbilirubinemia gastrointestinal symptom	Ritonivir (Norvir) gastrointestinal symptoms headache elevated ALT/AST taste perversion
Nelfinavir (Viracept) diarrhea nausea	Amprenavir (Angenerase) severe rash nausea/vomiting headache	Lopinavir/ritonivir (Kaletra) gastrointestinal symptoms headache weakness
Warrants discontinuation of all antiretrovirals

Protease Inhibitors

• Adverse effects are common. Other complications include hyperlipidemia, hyperglycemia, diabetes, and fat redistribution.