Sarah Battistich, MD, MSc, DTM&H

The US Centers for Disease Control and Prevention (CDC) estimates that 1.1 million people in the United States are living with HIV, with one in six of those individuals being unaware of their infection. Despite education and prevention efforts, each year approximately 50,000 people are newly infected. Less than 40% of people living with HIV are in regular care, and less than 25% are on antiretroviral therapy with a resultant suppressed viral load.¹ In 2010, 15,529 of these individuals died.² Although there have been great advances in the fight against HIV over the past several decades, the infection continues to be a major public health issue. 

Changing Landscape

Since its emergence in the 1980s as a disease of global significance, great strides have been made in recognition, testing, and treatment of HIV infection. While in many places in the world access to care and treatment are poor and opportunistic infections are still the primary cause of death for HIV-infected people, this landscape has changed dramatically in the United States (Figure 1). 

Highly active antiretroviral therapy (HAART) has decreased mortality associated with opportunistic infections, resulting in substantial increases in life expectancy.^3-5 In one single-center study conducted from 2000 to 2005, admissions due to opportunistic infections in HIV-positive individuals decreased, while those due to renal, oncologic, and psychiatric comorbidities as well as medication adverse events increased.⁶

In many ways, the advances in HIV therapy over the last decade have made the job of the emergency physician (EP) more challenging. While there are limited data on the idemiologic shift in ED presentations, the treatment of HIV-infected patients is no longer dominated by opportunistic infections and AIDS-defining illnesses. One must increasingly appreciate the predominance of noninfectious pathologies, such as cardiovascular disease (CVD), among an aging HIV-infected population. The increased life expectancy amongst patients compliant with HAART, combined with the changing demographics of people living with HIV trending towards older individuals, present an increasingly complex picture for the EP (Figure 2).

Routine Testing in the ED

In 2006, the CDC revised the guidelines for HIV testing in healthcare settings.⁷ The new recommendations included opt-out screening as an important strategy to assure HIV testing as a routine part of medical care. In April 2013, the US Preventive Services Task Force reinforced this message by issuing a grade A recommendation that clinicians test for HIV infection all adolescents and adults aged 15 to 65 years, including all pregnant women, as well as younger adolescents and older adults with risk factors for infection.

Subsequently, the number of EDs conducting HIV testing has substantially increased. Screening programs in the ED are a public health service and do result in important changes in clinical management of certain patients, but they can also present challenges. The institution of screening policies, such as opt-in versus opt-out testing, can be contentious and logistically difficult. A balanced presentation of these issues appears in the July 2011 issue of Annals of Emergency Medicine, which is focused on HIV screening in the ED.⁸

Fourth Generation HIV testing

Detecting HIV RNA is an expensive and laborious process, so screening and testing programs had relied on antibody-based assays. Until 2009, the third-generation antibody HIV assays available in the United States were effective in detecting chronic HIV infections but could not detect acute HIV infections (the period of time during which an individual is infected but has not yet produced antibodies). In June 2010, the US Food and Drug Administration approved fourth-generation tests that detect both antibodies and the p24 HIV antigen. The p24 antigen, a highly conserved capsid protein on the virus, is detectable early after infection and is associated with the initial burst of virus replication after infection. Levels of p24 start to drop approximately one month after infection, just at the point when antibody levels are usually detectable. Thus, the fourth-generation tests offer a substantial improvement in detection of early HIV infection. Estimates of the sensitivity of fourth-generation tests for early HIV infection vary. In two US studies, stored blood samples from people with acute infection were tested. Each sample tested positive for HIV RNA but negative for HIV antibodies. In the first study, 48 of 58 samples (82.7%) were correctly identified, whereas in the second study, 13 of 21 (61.9%) had a correct positive result.⁹ A German evaluation of 11 different fourth-generation tests found that the most sensitive test was positive 6.2 days after detection of RNA, while the least effective test identified infection 10.7 days later, a performance similar to that seen with third-generation tests.¹⁰

 

New clinical data from EDs also support the increased utility of fourth-generation testing. A recent study by Geren et al¹¹ found that in a nontargeted opt-out screening program with a fourth-generation antibody/antigen test, nearly one fourth of undiagnosed HIV patients had acute infections that would not have been diagnosed using older testing methods.¹¹ The results of this single study may not be generalizable, but they point out that routine testing of ED patients could lead to a substantial increase in the diagnosis of acute HIV infections and have a considerable impact on the recognition of HIV/AIDS infections that would otherwise go undiagnosed.

Advances in the ability to detect HIV infection should prompt clinicians to inquire about the testing methodologies available at their institutions. If fourth-generation testing is not available, and there is a clinical suspicion for early HIV infection, an RNA assay should be obtained.

The HIV-Positive Individual in the ED

Prior to the advent of HAART in 1995, the practice of emergency medicine required extensive knowledge of the recognition and treatment of opportunistic and nonopportunistic infections associated with HIV infection. Post-HAART, as patients with HIV live longer, and are exposed to antiretroviral therapy for extended periods, complaints unrelated to opportunistic infections are becoming more common. These complaints may be related to HIV infection and therapy, such as mental health disorders associated with chronic disease and side effects from antiretroviral therapy. Further, as HIV-infected individuals live longer, non-HIV related complaints common in the general population, such as CVD and oncologic disease, are increasingly relevant. To make matters even more challenging for the EP, antiretroviral therapy itself is associated with hyperlipidemia, hyperglycemia, truncal obesity, and a 26% increased relative risk of myocardial infarction (MI) per year.¹²

Patients with HIV presenting to the ED may have additional high risk social and medical factors with implications for care and follow-up. One retrospective single-center study of HIV-positive individuals found increased ED utilization was associated with lower income and higher viral load. Further, these patients sought care mainly for complaints unrelated to their HIV status. The most common diagnoses were ill-defined symptoms, injuries, and musculoskeletal disorders.¹³

Five Categories of HIV-related Presentations

HIV-positive individuals may present to the ED with complaints unrelated to their HIV status. However, amongst those with HIV-related presentations, it may be helpful to consider five basic categories: (1) HIV seroconversion syndrome; (2) opportunistic infections; (3) primary HIV-related diseases; (4) immune reconstitution syndrome; and (5) antiretroviral medication-related complaints.

HIV Seroconversion Syndrome

Seroconversion syndrome usually presents within the 3 to 4 weeks after HIV infection, and generally persists for 2 to 3 weeks. This seroconversion is accompanied by flu-like symptoms in at least 50%, and possibly up to 90%, of individuals. More than 50% will have at least one of the following symptoms: lymphadenopathy, fever, pharyngitis, rash, or myalgias. Additionally, there may be mucocutaneous lesions on the oral cavity and genitals. Other common symptoms include diarrhea, headache, nausea and vomiting, weight loss, thrush, and neurological symptoms such as aseptic meningitis, meningoencephalitis, facial palsy, and Guillain-Barré syndrome.

Seroconversion syndrome is often accompanied by a distinctive maculopapular, nonpruritic, erythematous rash on the face and trunk. The rash can affect the extremities including the palms and soles. The presence of this rash should trigger the consideration of HIV infection.

A diagnosis of HIV at seroconversion benefits the individual because it results in earlier treatment, but it additionally has a substantial public health impact. At this phase, viral loads are extremely high, and the patient is highly infectious. Individuals with acute HIV infection are thought to account for 7% to 50% of HIV transmission worldwide.^14-16

Opportunistic Infections and Primary HIV-related Diseases

Evaluation of the HIV-infected patient in the ED should be tailored to the individual complaint, with modifications for the relative immune status of the individual. It is advisable to consider the level of immune impairment, prior exposure to infectious agents, and the use of prophylactic therapy. A complete review of the opportunistic and primary HIV-related diseases in the contemporary ED is outside the scope of this review; however, several of the major considerations and most common diseases will be discussed.

In a patient with fever or other symptoms consistent with infection, basic diagnostic testing such as a complete blood count, metabolic panel, liver function tests, urinalysis, and chest radiography may need to be supplemented to account for opportunistic infections. Blood and urine cultures may need to include fungal and mycobacterial cultures as well as aerobic and anaerobic culture. Serologic testing for syphilis, toxoplasma, coccidiodes, and cryptococcal antigen may be merited.  If abdominal pain or diarrhea are reported, stool should be examined for parasites and their ova. When evaluating headache or any neurological complaints, the clinician should maintain a lower threshold for obtaining a computed tomography (CT) scan and lumbar puncture in immunocompromised patients.

 

Pneumocystis Jiroveci Pneumonia. Although HAART has markedly decreased its incidence, Pneumocystis jiroveci pneumonia (PJP), formerly Pneumocystis carinii pneumonia, remains the most common opportunistic infection amongst US patients with AIDS. The classic presentation of PJP is subacute. Fatigue, fever, and malaise associated with dry cough are common symptoms. Dyspnea, especially with exertion, is common. The classic chest X-ray finding in PJP is a diffuse, bilateral interstitial infiltrate. However, findings vary widely and can include lobar or nodular infiltrates, hilar lymphadenopathy, spontaneous pneumothorax, cavitation, and, rarely, pleural effusions. Furthermore, the chest X-ray findings may also be normal. Due to this varied presentation it is often difficult to reliably distinguish PJP from bacterial pneumonia or tuberculosis.

The special stains that are used to confirm the presence of Pneumocystis jiroveci in induced sputum or bronchoalveolar lavage usually are not available in the ED. Diagnosis and empirical treatment may hinge on the patient’s medical history and the presence of a CD4 count less than 200 cells/µL. An increase in the alveolar-arterial (A-a) oxygen gradient and an elevated lactate dehydrogenase level are both associated with a diagnosis of PJP pneumonia.

The drug of choice for PJP is intravenous (IV) trimethoprim/sulfamethoxazole (TMP-SMX) administered every 6 hours. The usual regimen is 15 to 20 mg/kg/d (based on the trimethoprim). For patients who cannot tolerate TMP-SMX, IV pentamidine (4 mg/kg once daily) is regarded as the second-line choice. Alternative treatment regimens include trimethoprim plus dapsone, and atovaquone. Steroids reduce the incidence of respiratory failure and mortality in those with a pulmonary partial pressure of oxygen, arterial less than 70 mm Hg or an A-a gradient greater than 35 mm Hg. Prednisone 40 mg orally twice a day should be used as adjunctive therapy for patients in this subgroup.

Mycobacterium Avium Complex. Mycobacterium avium complex (MAC) is a group of nontuberculous mycobacteria that cause one of the most common serious opportunistic infections in people with AIDS, and historically has affected almost exclusively individuals with CD4 counts <50 cells/µL. These mycobacteria are ubiquitous in the environment, including water and soil. Patients with disseminated MAC infections frequently have nonspecific symptoms, signs, and laboratory abnormalities. In many instances, worsening of chronic constitutional symptoms alone may reflect disseminated MAC infection and thus may be attributed incorrectly to the progression of other HIV-related illnesses. In a study at San Francisco General Hospital, a history of fever for >30 days, a hematocrit <30%, or a serum albumin level <3.0 g/dL were sensitive predictors of MAC bacteremia.¹⁷ However, severe fatigue, diarrhea, weight loss, neutropenia, and thrombocytopenia were not associated with MAC bacteremia.

Diagnosis is normally made by culturing the peripheral blood for mycobacteria. Performing two cultures yields a sensitivity of 98% for disseminated MAC. Acid-fast staining of tissue biopsies may also be useful, but is rarely a part of ED management.

The treatment regimen for disseminated MAC should include at least two drugs. The most efficacious therapies are the newer macrolide antibiotics clarithromycin and azithromycin. The preferred treatment regimen should include one of these agents along with ethambutol and/or rifabutin.

Cytomegalovirus Retinitis. Cytomegalovirus (CMV) retinitis accounts for up to 90% of HIV-related infectious retinopathies and is the most common cause of blindness in AIDS patients. Fortunately, HAART has reduced the incidence of this disease by 75% in AIDS patients; however, patients with a CD4 count <50 cells/µL are still at risk. Symptoms include blurred vision, floaters, photophobia, scotomata, or pain. Fundoscopic examination will reveal fluffy white retinal lesions. Although the appearance of CMV retinitis is usually sufficient to make the diagnosis, the differential is broad and includes HIV retinopathy, toxoplasmosis, syphilis, tuberculosis, pneumocystis, and cryptococcosis. The cornerstone of CMV retinitis therapy is reconstitution of the immune system with HAART, but parenteral and/or intravitreal antivirals such as ganciclovir should also be considered in consultation with an ophthalmologist.

Toxoplasmosis. Toxoplasma gondii is a leading cause of death attributed to foodborne illness in the United States. More than 60 million men, women, and children in the United States carry the toxoplasma parasite, but most are asymptomatic. This intracellular parasite is the leading cause of central nervous system (CNS) disease in patients with AIDS, with the greatest risk seen with CD4 counts <50 cells/µL, but occurring in those with CD4  counts <200 cells/µL as well. Symptoms may include headache, seizure, altered mental status, fever, or focal neurological deficits. Serologic testing for toxoplasma is not helpful due to the widespread presence of antibodies in the population. A contrast-enhanced CT scan typically reveals multiple ring-enhancing lesions.  Parasites can also be isolated from tissues and CSF. A brain biopsy is sometimes necessary to distinguish between toxoplasmosis and other causes of CNS disease such as CNS lymphoma. In general, therapy should not be delayed pending tissue diagnosis if imaging studies are consistent with toxoplasmosis. Standard therapy consists of pyrimethamine, sulfadiazene and folinic acid in combination. Trimethoprim-sulfamethoxazole (TMP-SMZ) can be used as an alternative regimen. Steroids may be merited and prophylactic antiepileptics may also be beneficial in those with significant mass effect from toxoplasma lesions.

 

Primary HIV-related Disease—Wasting Syndrome. The AIDS wasting syndrome is defined as a weight loss of at least 10% body weight in the presence of diarrhea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself. Before HAART, the prevalence of wasting was estimated to be up to 37%.¹⁸ Some data suggest that the incidence of wasting syndrome is decreasing, however other studies indicate that wasting remains a significant complication, even in populations with widespread access to effective antiretroviral therapy.¹⁹ Treatment is multifaceted, including pharmacologic agents to stimulate appetite and muscle accrual, and is not primarily within the purview of the ED. However, the EP should be aware of the process, and it may be prudent to screen for electrolyte disturbances and other treatable complications.

Immune Reconstitution Inflammatory Syndrome

The reconstitution of the immune system after the initiation of HAART can sometimes exacerbate the symptoms of previously quiescent opportunistic infections, producing a paradoxical worsening of the HIV patient’s clinical status. This state is referred to as immune reconstitution inflammatory syndrome (IRIS). Although mycobacterial infections such as tuberculosis and M avium complex are the most common infections associated with IRIS, nearly all opportunistic pathogens have been reported as underlying triggers. IRIS generally manifests within the first 8 weeks after the initiation of antiretroviral therapy. Therapy is largely supportive, may include anti-inflammatories and steroids, and is aimed at the inciting opportunistic agent.  Cessation of HAART is usually not required; however, in general these patients can become quite ill and often merit hospitalization.

Presentations Related to Complications of Antiretroviral Therapy

Hepatotoxicity and lactic acidosis are among the most common adverse reactions to antiretroviral therapy seen in the ED. All protease inhibitors are associated with hyperlipidemia, hyperglycemia, truncal obesity and an increased risk of atherosclerosis (Table). Multiple studies have shown that HIV infection and treatment with HAART increases an individual’s relative risk of acute MI. Patients receiving HAART should be considered to have an elevated risk of acute coronary syndromes, often at younger ages than the general population.²⁰

Postexposure Prophylaxis

There are two broad categories of postexposure prophylaxis (PEP) against HIV: occupational exposures (eg, needle stick injuries, conjunctival splashes) and nonoccupational exposures (eg, IV drug users, patients presenting after a sexual assault or a “high-risk” sexual encounter). Vertical, or mother-to-child transmission, is not primarily managed within the purview of the ED and will not be discussed here.

Although the considerations, counseling, and guidelines of these two types of exposures are different, the basic principles of PEP are the same. The US Public Health Service (USPHS) updated guidelines²¹ from 2013 include the following recommendations:

1.  Initiate antiretroviral therapy as soon as possible after exposure, ideally within 2 hours.  If the source patient’s HIV status is not known or immediately available, administration of PEP should not be delayed. After 72 hours there is little data to support the use of PEP, and it is not routinely recommended except on a case-by-case basis.

2.  A minimum three-drug regimen is recommended; although the most recent update to the USPHS guidelines for nonoccupational prophylaxis, made in 2005, suggest a two-drug regimen is sufficient, the majority of more recent national and regional guidelines recommend a three-drug regimen for both types of exposures.

3.  The PEP should continue for 28 days.

4.  Testing for other sexually-transmitted and blood-borne diseases such as hepatitis, syphilis, gonorrhea, and chlamydia should be considered. In women presenting after sexual assault, emergency contraception should be offered.

5.  Potential side effects should be discussed, and prophylactic therapy, such as antiemetics, should be considered for those initiating PEP.

Assessing Risk After a Potential Exposure

Many factors affect the risk of acquiring HIV after a single exposure. A number of epidemiologic studies have calculated the risk of HIV seroconversion after a single needle-stick injury from HIV-contaminated blood at around 0.3%.²² A meta-analysis in 2006 included 22 studies on accidental percutaneous injury with risk ranging from 0% to 2.38%, and concluded that the pooled estimate per exposure is 0.23%.Due to source patient factors and the type of exposure, the actual risk for a particular occupational exposure may be substantially higher or lower.²³

Despite the difficulties in assessing true risk to a particular individual after an exposure to HIV, pooled estimates are helpful in determining the cost-benefit analysis of PEP. According to the CDC, the risk of seroconversion after mucocutaneous exposure is thought to be 0.1%. There is considered to be no risk of HIV transmission where intact skin is exposed to HIV-infected blood. A case-control study in the late 1990s identified four factors that increased risk of transmission: deep injury, visible blood on the device causing injury, injury with a needle that had been placed in blood vessel, and advanced HIV-status of the source patient.²⁴

 

Additionally, source patient factors have a large impact on infectivity. Due to the presence of high HIV viral load levels, the probability of transmission in the first 6 months after HIV infection has been shown to be 8- to 12-fold higher than the risk associated with exposures that take place after the viral set point. One meta-analysis concluded that the infectivity of exposures from symptomatic AIDS patients are approximately double or triple the risk of a single percutaneous exposure compared to the risk from asymptomatic patients.²⁵

Similar to occupational exposures, many factors affect the risk of HIV acquisition from a nonoccupational exposure. With regard to sexual encounters, it is well established that the presence of other sexually transmitted infections in either partner increases transmission risk. Estimates for transmission risk between IV users range from 0.63% to 2.4%.²⁶ Transmission risk for all types of exposures is significantly decreased when the infected person is receiving effective antiretroviral therapy.

Occupational Exposures

Some studies indicate that over 50% of EPs have reported at least one occupational exposure to HIV in a 2-year period. After an occupational exposure, if the source patient is known to be HIV-infected, information about his/her viral load, antiretroviral medication history, and history of antiretroviral drug resistance should be obtained to assist in the selection of an optimal PEP regimen. If the source’s HIV screening test result is negative, but the individual may have been exposed to HIV in the past 4 to 8 weeks, a plasma HIV RNA assay should also be obtained. If these results are not immediately available, the first dose of PEP should not be delayed.

Nonoccupational Exposures

The data are not as robust, but there is increasing evidence that nonoccupational post exposure prophylaxis (nPEP) is both effective and feasible. The Department of Health and Human Services (DHHS) recommends the prompt initiation of nPEP HAART when persons seek care within 72 hours after exposure, the source is known to be HIV infected, and the exposure event presents a substantial risk for transmission. When the HIV status of the source is not known and the patient seeks care within 72 hours after exposure, the DHHS does not recommend for or against nPEP but encourages clinicians and patients to weigh the risks and benefits on a case-by-case basis. When the transmission risk is negligible or when patients seek care >72 hours after a substantial exposure, nPEP is not recommended except on a case-by-case basis at the discretion of the clinician.^27,28

Pre-exposure Prophylaxis

Pre-exposure prophylaxis, or PrEP, is a way for people who do not have HIV but who are at substantial risk of getting it to prevent HIV infection by taking an antiretroviral every day. Taking tenofivir or tenofivir plus emtricitabine (Truvada) daily has been shown to reduce by up to 92% the risk of acquiring HIV in heterosexual couples with one HIV-infected partner and by men who have sex with men (MSM).^29-31 A 2013 study provided the first evidence that PreP amongst injection drug users offers substantial protection against HIV acquisition.^29-32

On May 14, 2014, the USPHS released the first comprehensive clinical practice guidelines for PrEP, which include recommendations for daily fixed-dose combination of tenofovir and emtricitabine in people who engage in high risk sexual behaviors and for injection drug users. There is also a new tenofovir-eluting intravaginal ring that offered complete protection in a macaque monkey model of simian-HIV acquisition.³³ The human version of this intravaginal ring is currently undergoing phase I clinical trials in the United States and Kenya.

Conclusion

Even though great strides have been made in the education, prevention, and treatment of HIV/AIDS, it continues to be a major public health issue in the United States. As the life expectancy of individuals with an HIV-positive status has increased, these patients may present to the ED not only with symptoms related to HIV infection, but also with symptoms associated with nonrelated conditions, including adverse effects of HAART and other comorbidities. In addition, EPs should also have a high index of suspicion for HIV infection in previously undiagnosed patients presenting with symptoms associated with seroconversion syndrome—the early diagnosis of which will provide earlier recognition and treatment.

Dr Battistich is an assistant professor of emergency medicine, department of emergency medicine, New York University School of Medicine. She completed a fellowship in Global Health and International Emergency Medicine at Yale University.

The US Centers for Disease Control and Prevention (CDC) estimates that 1.1 million people in the United States are living with HIV, with one in six of those individuals being unaware of their infection. Despite education and prevention efforts, each year approximately 50,000 people are newly infected. Less than 40% of people living with HIV are in regular care, and less than 25% are on antiretroviral therapy with a resultant suppressed viral load.¹ In 2010, 15,529 of these individuals died.² Although there have been great advances in the fight against HIV over the past several decades, the infection continues to be a major public health issue. 

Changing Landscape

Since its emergence in the 1980s as a disease of global significance, great strides have been made in recognition, testing, and treatment of HIV infection. While in many places in the world access to care and treatment are poor and opportunistic infections are still the primary cause of death for HIV-infected people, this landscape has changed dramatically in the United States (Figure 1). 

Highly active antiretroviral therapy (HAART) has decreased mortality associated with opportunistic infections, resulting in substantial increases in life expectancy.^3-5 In one single-center study conducted from 2000 to 2005, admissions due to opportunistic infections in HIV-positive individuals decreased, while those due to renal, oncologic, and psychiatric comorbidities as well as medication adverse events increased.⁶

In many ways, the advances in HIV therapy over the last decade have made the job of the emergency physician (EP) more challenging. While there are limited data on the idemiologic shift in ED presentations, the treatment of HIV-infected patients is no longer dominated by opportunistic infections and AIDS-defining illnesses. One must increasingly appreciate the predominance of noninfectious pathologies, such as cardiovascular disease (CVD), among an aging HIV-infected population. The increased life expectancy amongst patients compliant with HAART, combined with the changing demographics of people living with HIV trending towards older individuals, present an increasingly complex picture for the EP (Figure 2).

Routine Testing in the ED

In 2006, the CDC revised the guidelines for HIV testing in healthcare settings.⁷ The new recommendations included opt-out screening as an important strategy to assure HIV testing as a routine part of medical care. In April 2013, the US Preventive Services Task Force reinforced this message by issuing a grade A recommendation that clinicians test for HIV infection all adolescents and adults aged 15 to 65 years, including all pregnant women, as well as younger adolescents and older adults with risk factors for infection.

Subsequently, the number of EDs conducting HIV testing has substantially increased. Screening programs in the ED are a public health service and do result in important changes in clinical management of certain patients, but they can also present challenges. The institution of screening policies, such as opt-in versus opt-out testing, can be contentious and logistically difficult. A balanced presentation of these issues appears in the July 2011 issue of Annals of Emergency Medicine, which is focused on HIV screening in the ED.⁸

Fourth Generation HIV testing

Detecting HIV RNA is an expensive and laborious process, so screening and testing programs had relied on antibody-based assays. Until 2009, the third-generation antibody HIV assays available in the United States were effective in detecting chronic HIV infections but could not detect acute HIV infections (the period of time during which an individual is infected but has not yet produced antibodies). In June 2010, the US Food and Drug Administration approved fourth-generation tests that detect both antibodies and the p24 HIV antigen. The p24 antigen, a highly conserved capsid protein on the virus, is detectable early after infection and is associated with the initial burst of virus replication after infection. Levels of p24 start to drop approximately one month after infection, just at the point when antibody levels are usually detectable. Thus, the fourth-generation tests offer a substantial improvement in detection of early HIV infection. Estimates of the sensitivity of fourth-generation tests for early HIV infection vary. In two US studies, stored blood samples from people with acute infection were tested. Each sample tested positive for HIV RNA but negative for HIV antibodies. In the first study, 48 of 58 samples (82.7%) were correctly identified, whereas in the second study, 13 of 21 (61.9%) had a correct positive result.⁹ A German evaluation of 11 different fourth-generation tests found that the most sensitive test was positive 6.2 days after detection of RNA, while the least effective test identified infection 10.7 days later, a performance similar to that seen with third-generation tests.¹⁰

 

New clinical data from EDs also support the increased utility of fourth-generation testing. A recent study by Geren et al¹¹ found that in a nontargeted opt-out screening program with a fourth-generation antibody/antigen test, nearly one fourth of undiagnosed HIV patients had acute infections that would not have been diagnosed using older testing methods.¹¹ The results of this single study may not be generalizable, but they point out that routine testing of ED patients could lead to a substantial increase in the diagnosis of acute HIV infections and have a considerable impact on the recognition of HIV/AIDS infections that would otherwise go undiagnosed.

Advances in the ability to detect HIV infection should prompt clinicians to inquire about the testing methodologies available at their institutions. If fourth-generation testing is not available, and there is a clinical suspicion for early HIV infection, an RNA assay should be obtained.

The HIV-Positive Individual in the ED

Prior to the advent of HAART in 1995, the practice of emergency medicine required extensive knowledge of the recognition and treatment of opportunistic and nonopportunistic infections associated with HIV infection. Post-HAART, as patients with HIV live longer, and are exposed to antiretroviral therapy for extended periods, complaints unrelated to opportunistic infections are becoming more common. These complaints may be related to HIV infection and therapy, such as mental health disorders associated with chronic disease and side effects from antiretroviral therapy. Further, as HIV-infected individuals live longer, non-HIV related complaints common in the general population, such as CVD and oncologic disease, are increasingly relevant. To make matters even more challenging for the EP, antiretroviral therapy itself is associated with hyperlipidemia, hyperglycemia, truncal obesity, and a 26% increased relative risk of myocardial infarction (MI) per year.¹²

Patients with HIV presenting to the ED may have additional high risk social and medical factors with implications for care and follow-up. One retrospective single-center study of HIV-positive individuals found increased ED utilization was associated with lower income and higher viral load. Further, these patients sought care mainly for complaints unrelated to their HIV status. The most common diagnoses were ill-defined symptoms, injuries, and musculoskeletal disorders.¹³

Five Categories of HIV-related Presentations

HIV-positive individuals may present to the ED with complaints unrelated to their HIV status. However, amongst those with HIV-related presentations, it may be helpful to consider five basic categories: (1) HIV seroconversion syndrome; (2) opportunistic infections; (3) primary HIV-related diseases; (4) immune reconstitution syndrome; and (5) antiretroviral medication-related complaints.

HIV Seroconversion Syndrome

Seroconversion syndrome usually presents within the 3 to 4 weeks after HIV infection, and generally persists for 2 to 3 weeks. This seroconversion is accompanied by flu-like symptoms in at least 50%, and possibly up to 90%, of individuals. More than 50% will have at least one of the following symptoms: lymphadenopathy, fever, pharyngitis, rash, or myalgias. Additionally, there may be mucocutaneous lesions on the oral cavity and genitals. Other common symptoms include diarrhea, headache, nausea and vomiting, weight loss, thrush, and neurological symptoms such as aseptic meningitis, meningoencephalitis, facial palsy, and Guillain-Barré syndrome.

Seroconversion syndrome is often accompanied by a distinctive maculopapular, nonpruritic, erythematous rash on the face and trunk. The rash can affect the extremities including the palms and soles. The presence of this rash should trigger the consideration of HIV infection.

A diagnosis of HIV at seroconversion benefits the individual because it results in earlier treatment, but it additionally has a substantial public health impact. At this phase, viral loads are extremely high, and the patient is highly infectious. Individuals with acute HIV infection are thought to account for 7% to 50% of HIV transmission worldwide.^14-16

Opportunistic Infections and Primary HIV-related Diseases

Evaluation of the HIV-infected patient in the ED should be tailored to the individual complaint, with modifications for the relative immune status of the individual. It is advisable to consider the level of immune impairment, prior exposure to infectious agents, and the use of prophylactic therapy. A complete review of the opportunistic and primary HIV-related diseases in the contemporary ED is outside the scope of this review; however, several of the major considerations and most common diseases will be discussed.

In a patient with fever or other symptoms consistent with infection, basic diagnostic testing such as a complete blood count, metabolic panel, liver function tests, urinalysis, and chest radiography may need to be supplemented to account for opportunistic infections. Blood and urine cultures may need to include fungal and mycobacterial cultures as well as aerobic and anaerobic culture. Serologic testing for syphilis, toxoplasma, coccidiodes, and cryptococcal antigen may be merited.  If abdominal pain or diarrhea are reported, stool should be examined for parasites and their ova. When evaluating headache or any neurological complaints, the clinician should maintain a lower threshold for obtaining a computed tomography (CT) scan and lumbar puncture in immunocompromised patients.

 

Pneumocystis Jiroveci Pneumonia. Although HAART has markedly decreased its incidence, Pneumocystis jiroveci pneumonia (PJP), formerly Pneumocystis carinii pneumonia, remains the most common opportunistic infection amongst US patients with AIDS. The classic presentation of PJP is subacute. Fatigue, fever, and malaise associated with dry cough are common symptoms. Dyspnea, especially with exertion, is common. The classic chest X-ray finding in PJP is a diffuse, bilateral interstitial infiltrate. However, findings vary widely and can include lobar or nodular infiltrates, hilar lymphadenopathy, spontaneous pneumothorax, cavitation, and, rarely, pleural effusions. Furthermore, the chest X-ray findings may also be normal. Due to this varied presentation it is often difficult to reliably distinguish PJP from bacterial pneumonia or tuberculosis.

The special stains that are used to confirm the presence of Pneumocystis jiroveci in induced sputum or bronchoalveolar lavage usually are not available in the ED. Diagnosis and empirical treatment may hinge on the patient’s medical history and the presence of a CD4 count less than 200 cells/µL. An increase in the alveolar-arterial (A-a) oxygen gradient and an elevated lactate dehydrogenase level are both associated with a diagnosis of PJP pneumonia.

The drug of choice for PJP is intravenous (IV) trimethoprim/sulfamethoxazole (TMP-SMX) administered every 6 hours. The usual regimen is 15 to 20 mg/kg/d (based on the trimethoprim). For patients who cannot tolerate TMP-SMX, IV pentamidine (4 mg/kg once daily) is regarded as the second-line choice. Alternative treatment regimens include trimethoprim plus dapsone, and atovaquone. Steroids reduce the incidence of respiratory failure and mortality in those with a pulmonary partial pressure of oxygen, arterial less than 70 mm Hg or an A-a gradient greater than 35 mm Hg. Prednisone 40 mg orally twice a day should be used as adjunctive therapy for patients in this subgroup.

Mycobacterium Avium Complex. Mycobacterium avium complex (MAC) is a group of nontuberculous mycobacteria that cause one of the most common serious opportunistic infections in people with AIDS, and historically has affected almost exclusively individuals with CD4 counts <50 cells/µL. These mycobacteria are ubiquitous in the environment, including water and soil. Patients with disseminated MAC infections frequently have nonspecific symptoms, signs, and laboratory abnormalities. In many instances, worsening of chronic constitutional symptoms alone may reflect disseminated MAC infection and thus may be attributed incorrectly to the progression of other HIV-related illnesses. In a study at San Francisco General Hospital, a history of fever for >30 days, a hematocrit <30%, or a serum albumin level <3.0 g/dL were sensitive predictors of MAC bacteremia.¹⁷ However, severe fatigue, diarrhea, weight loss, neutropenia, and thrombocytopenia were not associated with MAC bacteremia.

Diagnosis is normally made by culturing the peripheral blood for mycobacteria. Performing two cultures yields a sensitivity of 98% for disseminated MAC. Acid-fast staining of tissue biopsies may also be useful, but is rarely a part of ED management.

The treatment regimen for disseminated MAC should include at least two drugs. The most efficacious therapies are the newer macrolide antibiotics clarithromycin and azithromycin. The preferred treatment regimen should include one of these agents along with ethambutol and/or rifabutin.

Cytomegalovirus Retinitis. Cytomegalovirus (CMV) retinitis accounts for up to 90% of HIV-related infectious retinopathies and is the most common cause of blindness in AIDS patients. Fortunately, HAART has reduced the incidence of this disease by 75% in AIDS patients; however, patients with a CD4 count <50 cells/µL are still at risk. Symptoms include blurred vision, floaters, photophobia, scotomata, or pain. Fundoscopic examination will reveal fluffy white retinal lesions. Although the appearance of CMV retinitis is usually sufficient to make the diagnosis, the differential is broad and includes HIV retinopathy, toxoplasmosis, syphilis, tuberculosis, pneumocystis, and cryptococcosis. The cornerstone of CMV retinitis therapy is reconstitution of the immune system with HAART, but parenteral and/or intravitreal antivirals such as ganciclovir should also be considered in consultation with an ophthalmologist.

Toxoplasmosis. Toxoplasma gondii is a leading cause of death attributed to foodborne illness in the United States. More than 60 million men, women, and children in the United States carry the toxoplasma parasite, but most are asymptomatic. This intracellular parasite is the leading cause of central nervous system (CNS) disease in patients with AIDS, with the greatest risk seen with CD4 counts <50 cells/µL, but occurring in those with CD4  counts <200 cells/µL as well. Symptoms may include headache, seizure, altered mental status, fever, or focal neurological deficits. Serologic testing for toxoplasma is not helpful due to the widespread presence of antibodies in the population. A contrast-enhanced CT scan typically reveals multiple ring-enhancing lesions.  Parasites can also be isolated from tissues and CSF. A brain biopsy is sometimes necessary to distinguish between toxoplasmosis and other causes of CNS disease such as CNS lymphoma. In general, therapy should not be delayed pending tissue diagnosis if imaging studies are consistent with toxoplasmosis. Standard therapy consists of pyrimethamine, sulfadiazene and folinic acid in combination. Trimethoprim-sulfamethoxazole (TMP-SMZ) can be used as an alternative regimen. Steroids may be merited and prophylactic antiepileptics may also be beneficial in those with significant mass effect from toxoplasma lesions.

 

Primary HIV-related Disease—Wasting Syndrome. The AIDS wasting syndrome is defined as a weight loss of at least 10% body weight in the presence of diarrhea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself. Before HAART, the prevalence of wasting was estimated to be up to 37%.¹⁸ Some data suggest that the incidence of wasting syndrome is decreasing, however other studies indicate that wasting remains a significant complication, even in populations with widespread access to effective antiretroviral therapy.¹⁹ Treatment is multifaceted, including pharmacologic agents to stimulate appetite and muscle accrual, and is not primarily within the purview of the ED. However, the EP should be aware of the process, and it may be prudent to screen for electrolyte disturbances and other treatable complications.

Immune Reconstitution Inflammatory Syndrome

The reconstitution of the immune system after the initiation of HAART can sometimes exacerbate the symptoms of previously quiescent opportunistic infections, producing a paradoxical worsening of the HIV patient’s clinical status. This state is referred to as immune reconstitution inflammatory syndrome (IRIS). Although mycobacterial infections such as tuberculosis and M avium complex are the most common infections associated with IRIS, nearly all opportunistic pathogens have been reported as underlying triggers. IRIS generally manifests within the first 8 weeks after the initiation of antiretroviral therapy. Therapy is largely supportive, may include anti-inflammatories and steroids, and is aimed at the inciting opportunistic agent.  Cessation of HAART is usually not required; however, in general these patients can become quite ill and often merit hospitalization.

Presentations Related to Complications of Antiretroviral Therapy

Hepatotoxicity and lactic acidosis are among the most common adverse reactions to antiretroviral therapy seen in the ED. All protease inhibitors are associated with hyperlipidemia, hyperglycemia, truncal obesity and an increased risk of atherosclerosis (Table). Multiple studies have shown that HIV infection and treatment with HAART increases an individual’s relative risk of acute MI. Patients receiving HAART should be considered to have an elevated risk of acute coronary syndromes, often at younger ages than the general population.²⁰

Postexposure Prophylaxis

There are two broad categories of postexposure prophylaxis (PEP) against HIV: occupational exposures (eg, needle stick injuries, conjunctival splashes) and nonoccupational exposures (eg, IV drug users, patients presenting after a sexual assault or a “high-risk” sexual encounter). Vertical, or mother-to-child transmission, is not primarily managed within the purview of the ED and will not be discussed here.

Although the considerations, counseling, and guidelines of these two types of exposures are different, the basic principles of PEP are the same. The US Public Health Service (USPHS) updated guidelines²¹ from 2013 include the following recommendations:

1.  Initiate antiretroviral therapy as soon as possible after exposure, ideally within 2 hours.  If the source patient’s HIV status is not known or immediately available, administration of PEP should not be delayed. After 72 hours there is little data to support the use of PEP, and it is not routinely recommended except on a case-by-case basis.

2.  A minimum three-drug regimen is recommended; although the most recent update to the USPHS guidelines for nonoccupational prophylaxis, made in 2005, suggest a two-drug regimen is sufficient, the majority of more recent national and regional guidelines recommend a three-drug regimen for both types of exposures.

3.  The PEP should continue for 28 days.

4.  Testing for other sexually-transmitted and blood-borne diseases such as hepatitis, syphilis, gonorrhea, and chlamydia should be considered. In women presenting after sexual assault, emergency contraception should be offered.

5.  Potential side effects should be discussed, and prophylactic therapy, such as antiemetics, should be considered for those initiating PEP.

Assessing Risk After a Potential Exposure

Many factors affect the risk of acquiring HIV after a single exposure. A number of epidemiologic studies have calculated the risk of HIV seroconversion after a single needle-stick injury from HIV-contaminated blood at around 0.3%.²² A meta-analysis in 2006 included 22 studies on accidental percutaneous injury with risk ranging from 0% to 2.38%, and concluded that the pooled estimate per exposure is 0.23%.Due to source patient factors and the type of exposure, the actual risk for a particular occupational exposure may be substantially higher or lower.²³

Despite the difficulties in assessing true risk to a particular individual after an exposure to HIV, pooled estimates are helpful in determining the cost-benefit analysis of PEP. According to the CDC, the risk of seroconversion after mucocutaneous exposure is thought to be 0.1%. There is considered to be no risk of HIV transmission where intact skin is exposed to HIV-infected blood. A case-control study in the late 1990s identified four factors that increased risk of transmission: deep injury, visible blood on the device causing injury, injury with a needle that had been placed in blood vessel, and advanced HIV-status of the source patient.²⁴

 

Additionally, source patient factors have a large impact on infectivity. Due to the presence of high HIV viral load levels, the probability of transmission in the first 6 months after HIV infection has been shown to be 8- to 12-fold higher than the risk associated with exposures that take place after the viral set point. One meta-analysis concluded that the infectivity of exposures from symptomatic AIDS patients are approximately double or triple the risk of a single percutaneous exposure compared to the risk from asymptomatic patients.²⁵

Similar to occupational exposures, many factors affect the risk of HIV acquisition from a nonoccupational exposure. With regard to sexual encounters, it is well established that the presence of other sexually transmitted infections in either partner increases transmission risk. Estimates for transmission risk between IV users range from 0.63% to 2.4%.²⁶ Transmission risk for all types of exposures is significantly decreased when the infected person is receiving effective antiretroviral therapy.

Occupational Exposures

Some studies indicate that over 50% of EPs have reported at least one occupational exposure to HIV in a 2-year period. After an occupational exposure, if the source patient is known to be HIV-infected, information about his/her viral load, antiretroviral medication history, and history of antiretroviral drug resistance should be obtained to assist in the selection of an optimal PEP regimen. If the source’s HIV screening test result is negative, but the individual may have been exposed to HIV in the past 4 to 8 weeks, a plasma HIV RNA assay should also be obtained. If these results are not immediately available, the first dose of PEP should not be delayed.

Nonoccupational Exposures

The data are not as robust, but there is increasing evidence that nonoccupational post exposure prophylaxis (nPEP) is both effective and feasible. The Department of Health and Human Services (DHHS) recommends the prompt initiation of nPEP HAART when persons seek care within 72 hours after exposure, the source is known to be HIV infected, and the exposure event presents a substantial risk for transmission. When the HIV status of the source is not known and the patient seeks care within 72 hours after exposure, the DHHS does not recommend for or against nPEP but encourages clinicians and patients to weigh the risks and benefits on a case-by-case basis. When the transmission risk is negligible or when patients seek care >72 hours after a substantial exposure, nPEP is not recommended except on a case-by-case basis at the discretion of the clinician.^27,28

Pre-exposure Prophylaxis

Pre-exposure prophylaxis, or PrEP, is a way for people who do not have HIV but who are at substantial risk of getting it to prevent HIV infection by taking an antiretroviral every day. Taking tenofivir or tenofivir plus emtricitabine (Truvada) daily has been shown to reduce by up to 92% the risk of acquiring HIV in heterosexual couples with one HIV-infected partner and by men who have sex with men (MSM).^29-31 A 2013 study provided the first evidence that PreP amongst injection drug users offers substantial protection against HIV acquisition.^29-32

On May 14, 2014, the USPHS released the first comprehensive clinical practice guidelines for PrEP, which include recommendations for daily fixed-dose combination of tenofovir and emtricitabine in people who engage in high risk sexual behaviors and for injection drug users. There is also a new tenofovir-eluting intravaginal ring that offered complete protection in a macaque monkey model of simian-HIV acquisition.³³ The human version of this intravaginal ring is currently undergoing phase I clinical trials in the United States and Kenya.

Conclusion

Even though great strides have been made in the education, prevention, and treatment of HIV/AIDS, it continues to be a major public health issue in the United States. As the life expectancy of individuals with an HIV-positive status has increased, these patients may present to the ED not only with symptoms related to HIV infection, but also with symptoms associated with nonrelated conditions, including adverse effects of HAART and other comorbidities. In addition, EPs should also have a high index of suspicion for HIV infection in previously undiagnosed patients presenting with symptoms associated with seroconversion syndrome—the early diagnosis of which will provide earlier recognition and treatment.

Dr Battistich is an assistant professor of emergency medicine, department of emergency medicine, New York University School of Medicine. She completed a fellowship in Global Health and International Emergency Medicine at Yale University.

The US Centers for Disease Control and Prevention (CDC) estimates that 1.1 million people in the United States are living with HIV, with one in six of those individuals being unaware of their infection. Despite education and prevention efforts, each year approximately 50,000 people are newly infected. Less than 40% of people living with HIV are in regular care, and less than 25% are on antiretroviral therapy with a resultant suppressed viral load.¹ In 2010, 15,529 of these individuals died.² Although there have been great advances in the fight against HIV over the past several decades, the infection continues to be a major public health issue. 

Changing Landscape

Since its emergence in the 1980s as a disease of global significance, great strides have been made in recognition, testing, and treatment of HIV infection. While in many places in the world access to care and treatment are poor and opportunistic infections are still the primary cause of death for HIV-infected people, this landscape has changed dramatically in the United States (Figure 1). 

Highly active antiretroviral therapy (HAART) has decreased mortality associated with opportunistic infections, resulting in substantial increases in life expectancy.^3-5 In one single-center study conducted from 2000 to 2005, admissions due to opportunistic infections in HIV-positive individuals decreased, while those due to renal, oncologic, and psychiatric comorbidities as well as medication adverse events increased.⁶

In many ways, the advances in HIV therapy over the last decade have made the job of the emergency physician (EP) more challenging. While there are limited data on the idemiologic shift in ED presentations, the treatment of HIV-infected patients is no longer dominated by opportunistic infections and AIDS-defining illnesses. One must increasingly appreciate the predominance of noninfectious pathologies, such as cardiovascular disease (CVD), among an aging HIV-infected population. The increased life expectancy amongst patients compliant with HAART, combined with the changing demographics of people living with HIV trending towards older individuals, present an increasingly complex picture for the EP (Figure 2).

Routine Testing in the ED

In 2006, the CDC revised the guidelines for HIV testing in healthcare settings.⁷ The new recommendations included opt-out screening as an important strategy to assure HIV testing as a routine part of medical care. In April 2013, the US Preventive Services Task Force reinforced this message by issuing a grade A recommendation that clinicians test for HIV infection all adolescents and adults aged 15 to 65 years, including all pregnant women, as well as younger adolescents and older adults with risk factors for infection.

Subsequently, the number of EDs conducting HIV testing has substantially increased. Screening programs in the ED are a public health service and do result in important changes in clinical management of certain patients, but they can also present challenges. The institution of screening policies, such as opt-in versus opt-out testing, can be contentious and logistically difficult. A balanced presentation of these issues appears in the July 2011 issue of Annals of Emergency Medicine, which is focused on HIV screening in the ED.⁸

Fourth Generation HIV testing

Detecting HIV RNA is an expensive and laborious process, so screening and testing programs had relied on antibody-based assays. Until 2009, the third-generation antibody HIV assays available in the United States were effective in detecting chronic HIV infections but could not detect acute HIV infections (the period of time during which an individual is infected but has not yet produced antibodies). In June 2010, the US Food and Drug Administration approved fourth-generation tests that detect both antibodies and the p24 HIV antigen. The p24 antigen, a highly conserved capsid protein on the virus, is detectable early after infection and is associated with the initial burst of virus replication after infection. Levels of p24 start to drop approximately one month after infection, just at the point when antibody levels are usually detectable. Thus, the fourth-generation tests offer a substantial improvement in detection of early HIV infection. Estimates of the sensitivity of fourth-generation tests for early HIV infection vary. In two US studies, stored blood samples from people with acute infection were tested. Each sample tested positive for HIV RNA but negative for HIV antibodies. In the first study, 48 of 58 samples (82.7%) were correctly identified, whereas in the second study, 13 of 21 (61.9%) had a correct positive result.⁹ A German evaluation of 11 different fourth-generation tests found that the most sensitive test was positive 6.2 days after detection of RNA, while the least effective test identified infection 10.7 days later, a performance similar to that seen with third-generation tests.¹⁰

 

New clinical data from EDs also support the increased utility of fourth-generation testing. A recent study by Geren et al¹¹ found that in a nontargeted opt-out screening program with a fourth-generation antibody/antigen test, nearly one fourth of undiagnosed HIV patients had acute infections that would not have been diagnosed using older testing methods.¹¹ The results of this single study may not be generalizable, but they point out that routine testing of ED patients could lead to a substantial increase in the diagnosis of acute HIV infections and have a considerable impact on the recognition of HIV/AIDS infections that would otherwise go undiagnosed.

Advances in the ability to detect HIV infection should prompt clinicians to inquire about the testing methodologies available at their institutions. If fourth-generation testing is not available, and there is a clinical suspicion for early HIV infection, an RNA assay should be obtained.

The HIV-Positive Individual in the ED

Prior to the advent of HAART in 1995, the practice of emergency medicine required extensive knowledge of the recognition and treatment of opportunistic and nonopportunistic infections associated with HIV infection. Post-HAART, as patients with HIV live longer, and are exposed to antiretroviral therapy for extended periods, complaints unrelated to opportunistic infections are becoming more common. These complaints may be related to HIV infection and therapy, such as mental health disorders associated with chronic disease and side effects from antiretroviral therapy. Further, as HIV-infected individuals live longer, non-HIV related complaints common in the general population, such as CVD and oncologic disease, are increasingly relevant. To make matters even more challenging for the EP, antiretroviral therapy itself is associated with hyperlipidemia, hyperglycemia, truncal obesity, and a 26% increased relative risk of myocardial infarction (MI) per year.¹²

Patients with HIV presenting to the ED may have additional high risk social and medical factors with implications for care and follow-up. One retrospective single-center study of HIV-positive individuals found increased ED utilization was associated with lower income and higher viral load. Further, these patients sought care mainly for complaints unrelated to their HIV status. The most common diagnoses were ill-defined symptoms, injuries, and musculoskeletal disorders.¹³

Five Categories of HIV-related Presentations

HIV-positive individuals may present to the ED with complaints unrelated to their HIV status. However, amongst those with HIV-related presentations, it may be helpful to consider five basic categories: (1) HIV seroconversion syndrome; (2) opportunistic infections; (3) primary HIV-related diseases; (4) immune reconstitution syndrome; and (5) antiretroviral medication-related complaints.

HIV Seroconversion Syndrome

Seroconversion syndrome usually presents within the 3 to 4 weeks after HIV infection, and generally persists for 2 to 3 weeks. This seroconversion is accompanied by flu-like symptoms in at least 50%, and possibly up to 90%, of individuals. More than 50% will have at least one of the following symptoms: lymphadenopathy, fever, pharyngitis, rash, or myalgias. Additionally, there may be mucocutaneous lesions on the oral cavity and genitals. Other common symptoms include diarrhea, headache, nausea and vomiting, weight loss, thrush, and neurological symptoms such as aseptic meningitis, meningoencephalitis, facial palsy, and Guillain-Barré syndrome.

Seroconversion syndrome is often accompanied by a distinctive maculopapular, nonpruritic, erythematous rash on the face and trunk. The rash can affect the extremities including the palms and soles. The presence of this rash should trigger the consideration of HIV infection.

A diagnosis of HIV at seroconversion benefits the individual because it results in earlier treatment, but it additionally has a substantial public health impact. At this phase, viral loads are extremely high, and the patient is highly infectious. Individuals with acute HIV infection are thought to account for 7% to 50% of HIV transmission worldwide.^14-16

Opportunistic Infections and Primary HIV-related Diseases

Evaluation of the HIV-infected patient in the ED should be tailored to the individual complaint, with modifications for the relative immune status of the individual. It is advisable to consider the level of immune impairment, prior exposure to infectious agents, and the use of prophylactic therapy. A complete review of the opportunistic and primary HIV-related diseases in the contemporary ED is outside the scope of this review; however, several of the major considerations and most common diseases will be discussed.

In a patient with fever or other symptoms consistent with infection, basic diagnostic testing such as a complete blood count, metabolic panel, liver function tests, urinalysis, and chest radiography may need to be supplemented to account for opportunistic infections. Blood and urine cultures may need to include fungal and mycobacterial cultures as well as aerobic and anaerobic culture. Serologic testing for syphilis, toxoplasma, coccidiodes, and cryptococcal antigen may be merited.  If abdominal pain or diarrhea are reported, stool should be examined for parasites and their ova. When evaluating headache or any neurological complaints, the clinician should maintain a lower threshold for obtaining a computed tomography (CT) scan and lumbar puncture in immunocompromised patients.

 

Pneumocystis Jiroveci Pneumonia. Although HAART has markedly decreased its incidence, Pneumocystis jiroveci pneumonia (PJP), formerly Pneumocystis carinii pneumonia, remains the most common opportunistic infection amongst US patients with AIDS. The classic presentation of PJP is subacute. Fatigue, fever, and malaise associated with dry cough are common symptoms. Dyspnea, especially with exertion, is common. The classic chest X-ray finding in PJP is a diffuse, bilateral interstitial infiltrate. However, findings vary widely and can include lobar or nodular infiltrates, hilar lymphadenopathy, spontaneous pneumothorax, cavitation, and, rarely, pleural effusions. Furthermore, the chest X-ray findings may also be normal. Due to this varied presentation it is often difficult to reliably distinguish PJP from bacterial pneumonia or tuberculosis.

The special stains that are used to confirm the presence of Pneumocystis jiroveci in induced sputum or bronchoalveolar lavage usually are not available in the ED. Diagnosis and empirical treatment may hinge on the patient’s medical history and the presence of a CD4 count less than 200 cells/µL. An increase in the alveolar-arterial (A-a) oxygen gradient and an elevated lactate dehydrogenase level are both associated with a diagnosis of PJP pneumonia.

The drug of choice for PJP is intravenous (IV) trimethoprim/sulfamethoxazole (TMP-SMX) administered every 6 hours. The usual regimen is 15 to 20 mg/kg/d (based on the trimethoprim). For patients who cannot tolerate TMP-SMX, IV pentamidine (4 mg/kg once daily) is regarded as the second-line choice. Alternative treatment regimens include trimethoprim plus dapsone, and atovaquone. Steroids reduce the incidence of respiratory failure and mortality in those with a pulmonary partial pressure of oxygen, arterial less than 70 mm Hg or an A-a gradient greater than 35 mm Hg. Prednisone 40 mg orally twice a day should be used as adjunctive therapy for patients in this subgroup.

Mycobacterium Avium Complex. Mycobacterium avium complex (MAC) is a group of nontuberculous mycobacteria that cause one of the most common serious opportunistic infections in people with AIDS, and historically has affected almost exclusively individuals with CD4 counts <50 cells/µL. These mycobacteria are ubiquitous in the environment, including water and soil. Patients with disseminated MAC infections frequently have nonspecific symptoms, signs, and laboratory abnormalities. In many instances, worsening of chronic constitutional symptoms alone may reflect disseminated MAC infection and thus may be attributed incorrectly to the progression of other HIV-related illnesses. In a study at San Francisco General Hospital, a history of fever for >30 days, a hematocrit <30%, or a serum albumin level <3.0 g/dL were sensitive predictors of MAC bacteremia.¹⁷ However, severe fatigue, diarrhea, weight loss, neutropenia, and thrombocytopenia were not associated with MAC bacteremia.

Diagnosis is normally made by culturing the peripheral blood for mycobacteria. Performing two cultures yields a sensitivity of 98% for disseminated MAC. Acid-fast staining of tissue biopsies may also be useful, but is rarely a part of ED management.

The treatment regimen for disseminated MAC should include at least two drugs. The most efficacious therapies are the newer macrolide antibiotics clarithromycin and azithromycin. The preferred treatment regimen should include one of these agents along with ethambutol and/or rifabutin.

Cytomegalovirus Retinitis. Cytomegalovirus (CMV) retinitis accounts for up to 90% of HIV-related infectious retinopathies and is the most common cause of blindness in AIDS patients. Fortunately, HAART has reduced the incidence of this disease by 75% in AIDS patients; however, patients with a CD4 count <50 cells/µL are still at risk. Symptoms include blurred vision, floaters, photophobia, scotomata, or pain. Fundoscopic examination will reveal fluffy white retinal lesions. Although the appearance of CMV retinitis is usually sufficient to make the diagnosis, the differential is broad and includes HIV retinopathy, toxoplasmosis, syphilis, tuberculosis, pneumocystis, and cryptococcosis. The cornerstone of CMV retinitis therapy is reconstitution of the immune system with HAART, but parenteral and/or intravitreal antivirals such as ganciclovir should also be considered in consultation with an ophthalmologist.

Toxoplasmosis. Toxoplasma gondii is a leading cause of death attributed to foodborne illness in the United States. More than 60 million men, women, and children in the United States carry the toxoplasma parasite, but most are asymptomatic. This intracellular parasite is the leading cause of central nervous system (CNS) disease in patients with AIDS, with the greatest risk seen with CD4 counts <50 cells/µL, but occurring in those with CD4  counts <200 cells/µL as well. Symptoms may include headache, seizure, altered mental status, fever, or focal neurological deficits. Serologic testing for toxoplasma is not helpful due to the widespread presence of antibodies in the population. A contrast-enhanced CT scan typically reveals multiple ring-enhancing lesions.  Parasites can also be isolated from tissues and CSF. A brain biopsy is sometimes necessary to distinguish between toxoplasmosis and other causes of CNS disease such as CNS lymphoma. In general, therapy should not be delayed pending tissue diagnosis if imaging studies are consistent with toxoplasmosis. Standard therapy consists of pyrimethamine, sulfadiazene and folinic acid in combination. Trimethoprim-sulfamethoxazole (TMP-SMZ) can be used as an alternative regimen. Steroids may be merited and prophylactic antiepileptics may also be beneficial in those with significant mass effect from toxoplasma lesions.

 

Primary HIV-related Disease—Wasting Syndrome. The AIDS wasting syndrome is defined as a weight loss of at least 10% body weight in the presence of diarrhea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself. Before HAART, the prevalence of wasting was estimated to be up to 37%.¹⁸ Some data suggest that the incidence of wasting syndrome is decreasing, however other studies indicate that wasting remains a significant complication, even in populations with widespread access to effective antiretroviral therapy.¹⁹ Treatment is multifaceted, including pharmacologic agents to stimulate appetite and muscle accrual, and is not primarily within the purview of the ED. However, the EP should be aware of the process, and it may be prudent to screen for electrolyte disturbances and other treatable complications.

Immune Reconstitution Inflammatory Syndrome

The reconstitution of the immune system after the initiation of HAART can sometimes exacerbate the symptoms of previously quiescent opportunistic infections, producing a paradoxical worsening of the HIV patient’s clinical status. This state is referred to as immune reconstitution inflammatory syndrome (IRIS). Although mycobacterial infections such as tuberculosis and M avium complex are the most common infections associated with IRIS, nearly all opportunistic pathogens have been reported as underlying triggers. IRIS generally manifests within the first 8 weeks after the initiation of antiretroviral therapy. Therapy is largely supportive, may include anti-inflammatories and steroids, and is aimed at the inciting opportunistic agent.  Cessation of HAART is usually not required; however, in general these patients can become quite ill and often merit hospitalization.

Presentations Related to Complications of Antiretroviral Therapy

Hepatotoxicity and lactic acidosis are among the most common adverse reactions to antiretroviral therapy seen in the ED. All protease inhibitors are associated with hyperlipidemia, hyperglycemia, truncal obesity and an increased risk of atherosclerosis (Table). Multiple studies have shown that HIV infection and treatment with HAART increases an individual’s relative risk of acute MI. Patients receiving HAART should be considered to have an elevated risk of acute coronary syndromes, often at younger ages than the general population.²⁰

Postexposure Prophylaxis

There are two broad categories of postexposure prophylaxis (PEP) against HIV: occupational exposures (eg, needle stick injuries, conjunctival splashes) and nonoccupational exposures (eg, IV drug users, patients presenting after a sexual assault or a “high-risk” sexual encounter). Vertical, or mother-to-child transmission, is not primarily managed within the purview of the ED and will not be discussed here.

Although the considerations, counseling, and guidelines of these two types of exposures are different, the basic principles of PEP are the same. The US Public Health Service (USPHS) updated guidelines²¹ from 2013 include the following recommendations:

1.  Initiate antiretroviral therapy as soon as possible after exposure, ideally within 2 hours.  If the source patient’s HIV status is not known or immediately available, administration of PEP should not be delayed. After 72 hours there is little data to support the use of PEP, and it is not routinely recommended except on a case-by-case basis.

2.  A minimum three-drug regimen is recommended; although the most recent update to the USPHS guidelines for nonoccupational prophylaxis, made in 2005, suggest a two-drug regimen is sufficient, the majority of more recent national and regional guidelines recommend a three-drug regimen for both types of exposures.

3.  The PEP should continue for 28 days.

4.  Testing for other sexually-transmitted and blood-borne diseases such as hepatitis, syphilis, gonorrhea, and chlamydia should be considered. In women presenting after sexual assault, emergency contraception should be offered.

5.  Potential side effects should be discussed, and prophylactic therapy, such as antiemetics, should be considered for those initiating PEP.

Assessing Risk After a Potential Exposure

Many factors affect the risk of acquiring HIV after a single exposure. A number of epidemiologic studies have calculated the risk of HIV seroconversion after a single needle-stick injury from HIV-contaminated blood at around 0.3%.²² A meta-analysis in 2006 included 22 studies on accidental percutaneous injury with risk ranging from 0% to 2.38%, and concluded that the pooled estimate per exposure is 0.23%.Due to source patient factors and the type of exposure, the actual risk for a particular occupational exposure may be substantially higher or lower.²³

Despite the difficulties in assessing true risk to a particular individual after an exposure to HIV, pooled estimates are helpful in determining the cost-benefit analysis of PEP. According to the CDC, the risk of seroconversion after mucocutaneous exposure is thought to be 0.1%. There is considered to be no risk of HIV transmission where intact skin is exposed to HIV-infected blood. A case-control study in the late 1990s identified four factors that increased risk of transmission: deep injury, visible blood on the device causing injury, injury with a needle that had been placed in blood vessel, and advanced HIV-status of the source patient.²⁴

 

Additionally, source patient factors have a large impact on infectivity. Due to the presence of high HIV viral load levels, the probability of transmission in the first 6 months after HIV infection has been shown to be 8- to 12-fold higher than the risk associated with exposures that take place after the viral set point. One meta-analysis concluded that the infectivity of exposures from symptomatic AIDS patients are approximately double or triple the risk of a single percutaneous exposure compared to the risk from asymptomatic patients.²⁵

Similar to occupational exposures, many factors affect the risk of HIV acquisition from a nonoccupational exposure. With regard to sexual encounters, it is well established that the presence of other sexually transmitted infections in either partner increases transmission risk. Estimates for transmission risk between IV users range from 0.63% to 2.4%.²⁶ Transmission risk for all types of exposures is significantly decreased when the infected person is receiving effective antiretroviral therapy.

Occupational Exposures

Some studies indicate that over 50% of EPs have reported at least one occupational exposure to HIV in a 2-year period. After an occupational exposure, if the source patient is known to be HIV-infected, information about his/her viral load, antiretroviral medication history, and history of antiretroviral drug resistance should be obtained to assist in the selection of an optimal PEP regimen. If the source’s HIV screening test result is negative, but the individual may have been exposed to HIV in the past 4 to 8 weeks, a plasma HIV RNA assay should also be obtained. If these results are not immediately available, the first dose of PEP should not be delayed.

Nonoccupational Exposures

The data are not as robust, but there is increasing evidence that nonoccupational post exposure prophylaxis (nPEP) is both effective and feasible. The Department of Health and Human Services (DHHS) recommends the prompt initiation of nPEP HAART when persons seek care within 72 hours after exposure, the source is known to be HIV infected, and the exposure event presents a substantial risk for transmission. When the HIV status of the source is not known and the patient seeks care within 72 hours after exposure, the DHHS does not recommend for or against nPEP but encourages clinicians and patients to weigh the risks and benefits on a case-by-case basis. When the transmission risk is negligible or when patients seek care >72 hours after a substantial exposure, nPEP is not recommended except on a case-by-case basis at the discretion of the clinician.^27,28

Pre-exposure Prophylaxis

Pre-exposure prophylaxis, or PrEP, is a way for people who do not have HIV but who are at substantial risk of getting it to prevent HIV infection by taking an antiretroviral every day. Taking tenofivir or tenofivir plus emtricitabine (Truvada) daily has been shown to reduce by up to 92% the risk of acquiring HIV in heterosexual couples with one HIV-infected partner and by men who have sex with men (MSM).^29-31 A 2013 study provided the first evidence that PreP amongst injection drug users offers substantial protection against HIV acquisition.^29-32

On May 14, 2014, the USPHS released the first comprehensive clinical practice guidelines for PrEP, which include recommendations for daily fixed-dose combination of tenofovir and emtricitabine in people who engage in high risk sexual behaviors and for injection drug users. There is also a new tenofovir-eluting intravaginal ring that offered complete protection in a macaque monkey model of simian-HIV acquisition.³³ The human version of this intravaginal ring is currently undergoing phase I clinical trials in the United States and Kenya.

Conclusion

Even though great strides have been made in the education, prevention, and treatment of HIV/AIDS, it continues to be a major public health issue in the United States. As the life expectancy of individuals with an HIV-positive status has increased, these patients may present to the ED not only with symptoms related to HIV infection, but also with symptoms associated with nonrelated conditions, including adverse effects of HAART and other comorbidities. In addition, EPs should also have a high index of suspicion for HIV infection in previously undiagnosed patients presenting with symptoms associated with seroconversion syndrome—the early diagnosis of which will provide earlier recognition and treatment.

Dr Battistich is an assistant professor of emergency medicine, department of emergency medicine, New York University School of Medicine. She completed a fellowship in Global Health and International Emergency Medicine at Yale University.