Learning Objectives: After completing this CME activity, the physician should be better able to:
1. Evaluate highly active antiretroviral therapy (HAART) for reducing rates of opportunistic infection in HIV-positive patients, which increases late-stage complications of HIV infection.
2. Formulate a plan to counter adverse reactions to HAART therapy and drug-drug interactions between HAART and other medications when treating HIV-positive patients.
3. Demonstrate that HIV infection, especially when treated with protease inhibitors, is a major risk factor for atherosclerotic vascular disease.
Article from the 2010 LLSA Reading List:
Care of the HIV-Positive Patient in the Emergency Department in the Era of Highly Active Antiretroviral Therapy
Venkat A, Piontkowsky DM, et al
Ann Emerg Med
The authors of this comprehensive review describe the myriad ways that patients with human immunodeficiency virus present to the emergency department, emphasizing conditions more prevalent in the era of highly active antiretroviral therapy (HAART). As patients with HIV live longer with fewer opportunistic infections, more complex medication regimens, and more coexisting chronic illness, evaluating these patients has shifted from finding opportunistic infections to identifying noninfectious illnesses.
Because the patient with chronic HIV infection can present with such a broad range of illness, the authors take an organ-based approach in cataloging emergency conditions prevalent in these patients. After reading this article, clinicians should be better able to evaluate how HAART reduces opportunistic infection in HIV-positive patients but increases late-stage complications of HIV infection, formulate a plan to counter adverse reactions to HAART therapy and drug-drug interactions between HAART and other medications, and demonstrate that HIV infection, especially when treated with protease inhibitors, is a major risk factor for atherosclerotic vascular disease.
The authors describe typical HAART regimens and criteria for starting therapy because not all patients with HIV infection need to be on antiretroviral therapy (e.g., CD4 count greater than 350 and otherwise healthy). They discuss adverse effects of various antiretroviral medications, two of the most important of which are hepatotoxicity, ranging from mild transaminase increases to fulminant hepatic failure, and lactic acidosis due to mitochondrial toxicity. Early symptoms of both conditions are likely to be subtle and nonspecific, so high clinical suspicion is warranted.
The authors also address drug-drug interactions between HAART medications (usually protease inhibitors) and non-HAART medications. The list of significant interactions is extensive, and includes commonly used medications such as the cardiac drugs diltiazem, metoprolol, warfarin, digoxin, and amiodarone, anticonvulsants, and antilipid agents such as atorvastatin, lovastatin, and simvastatin. According to the authors, pravastatin is the antilipid agent of choice for patients on HAART.
Immune reconstitution inflammatory syndrome (IRIS) occurs after effective HAART therapy is initiated, in which the revived immune system develops an overly exuberant inflammatory response to a pre-existing pathogen that had been dormant. As the authors note, the most common trigger for IRIS is Mycobacterium avium-intracellulare (MAI), which may result in multiorgan involvement. This typically occurs within eight weeks of starting HAART, and is often self-limited but may be treated with corticosteroids if symptoms persist or threaten organ function.
Cardiovascular: Protease inhibitor use and HIV infection are major risk factors for developing atherosclerotic coronary artery disease, some of which is mediated through metabolic effects on lipid profiles. Long-term HIV infection is also a risk factor for developing diabetes mellitus, adding to atherosclerosis risk. The authors cite studies showing up to 75 percent increased incidence of myocardial infarction associated with HIV infection. (J Clin Endocrinol Metab 2007;92:2506), with a relative increase of 16 percent per year of protease inhibitor exposure. (N Engl J Med 2007;356:1723.) HIV infection, especially when treated with a protease inhibitor-based regimen, should be considered a major risk factor for coronary artery disease. On the other hand, dilated cardiomyopathy has become a much more uncommon manifestation of HIV infection in the HAART era.
Pulmonary: The epidemiology of HIV-related lung disease has changed drastically with HAART. Opportunistic pneumonias such as Pneumocystis used to dominate, but the most common pathogen now in HIV patients with pneumonia is Streptococcus pneumoniae, just as in the general population. Long-term HIV infection seems to predispose patients to COPD, and is known to cause pulmonary arterial hypertension in the absence of primary lung pathology.
Neurologic: HAART therapy's impact on neurologic disease is similar to the epidemiological changes on pulmonary disease. The incidence of CNS lymphoma and opportunistic CNS infections with Toxoplasma and Cryptococcus has decreased primarily due to HAART-related immune reconstitution. In their place are increasing rates of cerebrovascular disease and stroke and increasing incidence of polyneuropathy, either from the virus itself or the antiretroviral agents used.
Renal: Primary nephropathy from the HIV virus itself, toxicity from HAART medications, and complications of other HIV-related diseases (e.g., diabetes) may cause acute or chronic renal failure. The authors also note that the protease inhibitors indinavir and atazanavir are associated with urolithiasis, and may produce radiolucent stones.
GI/Hepatic: The authors note that HAART therapy effectively reduces the incidence of Candida esophagitis and Cryptosporidium diarrhea, two of the most common scourges of the pre-HAART era. Instead, acute diarrhea in HIV patients may now be approached in a similar fashion to the general population, with special attention to the possibility of Clostridium difficile infection. Very commonly, HIV patients also are infected with hepatitis B or C, complicating not only treatment regimens and responses to therapy, but accelerating the course of the HIV and hepatitis virus infections. As the authors note, the liver is commonly the target of HAART-related drug toxicity, and hepatitis virus co-infection increases that risk.
Hematologic-Oncologic: While the incidence of Kaposi's sarcoma is greatly reduced in the HAART era, other malignancies are becoming more common, such as Hodgkin's disease, anal cancer, and primary lung cancer. Numerous hematologic abnormalities may be associated with HIV infection and with HAART, most commonly macrocytic anemia due to zidovudine. Importantly, venous thromboembolic disease also appears to be more common in patients with long-term HIV infection; the authors note an incidence up to 10 times greater than that of the general population.
Psychiatric: According to the authors, depression is common in HIV patients, with a prevalence of 40 percent. Depression may impair compliance with medication, and should be differentiated from more serious cognitive impairments such as AIDS dementia or mania. HAART regimens containing efavirenz may lead to prominent neuropsychiatric effects such as vivid dreams or even frank psychosis within the first four weeks of therapy.
Musculoskeletal: The incidence of osteoporosis and osteonecrosis in patients with long-term HIV infection is increasing, as is a predisposition to bacterial infections of bones, intervertebral discs, and muscles, particularly in the thigh. In addition, they note the greatly increased risk of rhabdomyolysis in patients on HAART who are also treated with statin medications.
Dermatologic: Many common skin ailments persist in the patient with long-term HIV infection, usually related to impaired local immunity or co-infection. It is important to recognize the hypersensitivity reaction to abacavir, which presents with a macular rash, fever, and abnormalities of liver tests, and also may cause lymphopenia, elevated CK levels, and hypotension. It is critical that a patient with such a reaction to abacavir never take the drug again because another challenge may be fatal.
Comment: The development of HAART for treating HIV infection is one of the greatest triumphs of modern medicine, and has revolutionized HIV treatment over the past 14 years. While HIV seroconversion was once tantamount to a death sentence for patients, the disease is now eminently treatable and controllable, sometimes with just a few pills once a day. For many patients, HIV infection is a chronic disease similar to diabetes mellitus; it requires lifestyle changes and medication compliance, and carries increased risk of vascular, renal, and neurologic disease, but it is not a death sentence. Since the advent of protease inhibitors in 1996, HAART regimens have become increasingly safe and convenient, and most patients with HIV can be treated when therapy is indicated.
It is also important to note that two groups of ED patients will not be on HAART medications. The first is the patient with primary HIV seroconversion illness. This may mimic a flu-like or viral syndrome with rash, joint pain, fever, and lymphadenopathy. It can occur two to four weeks after exposure, and is not detectable by standard HIV screening tests. Patients with symptoms and a history of high-risk exposure should be referred for PCR-based direct viral detection testing (viral load) to allow for early treatment and to protect potential partners. EPs also can make a difference in the second group of patients, who present with HIV- or AIDS-related illness without a known diagnosis.
Patients who do not seek routine testing or get tested via other means (blood donation, pregnancy, military service) will not typically have symptoms until profound immune suppression yields opportunistic malignancy or infection. In addition to the obvious suspects, such as patients with Kaposi's sarcoma or Pneumocystis pneumonia, consider referral for HIV testing in patients with unexplained hematologic abnormalities, thrush, diffuse lymphadenopathy or onychomycosis, seborrheic dermatitis, herpes zoster, or any suspicion of other sexually transmitted disease. If rapid HIV testing is not available, one useful screening tool is the absolute lymphocyte count; values less than 1000 per microliter are associated with CD4 counts less than 200 in patients suspected of having HIV or AIDS. (Ann Emerg Med 1998;32[3 Pt 1]:323.) An appropriate suspicion of a low CD4 count can help direct initial testing and therapy in acutely ill patients even before HIV status can be confirmed.
CME Participation Instructions
To earn CME credit, you must read the article in Emergency Medicine News, and complete the evaluation questions and quiz, answering at least 80 percent of the questions correctly. Mail the completed quiz with your check for $12 payable to Lippincott Continuing Medical Education Institute, Inc., Two Commerce Square, 2001 Market St., Third Fl., Philadelphia, PA 19103. Only the first entry will be considered for credit, and must be received by Lippincott Continuing Medical Education Institute by August 31, 2011. Acknowledgment will be sent to you within six to eight weeks of participation.
Lippincott Continuing Medical Education Institute is accredited by the Accreditation Council for Continuing Medical Education to provide medical education to physicians. Lippincott Continuing Medical Education Institute designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activities.
Luis M. Lovato, MD, an Associate Professor at the David Geffen School of Medicine at UCLA, the Director of Critical Care in the Department of Emergency Medicine at Olive View-UCLA Medical Center, and an instructor for the National MegaLLSA Review Course (www.megallsa.com), serves as the medical editor of this column.