Human immunodeficiency virus and acquired immune deficiency syndrome

Essentials

1
Patients with previously undiagnosed human immunodeficiency virus (HIV) infection may present to the emergency department at any time during the course of infection, from early (seroconversion) to late acquired immune deficiency syndrome ([AIDS]-defining illness) stages.
2
Patients with previously diagnosed HIV infection may present with complications of anti-retroviral therapy or, if therapy has failed or is not taken, with a range of HIV-related clinical syndromes.
3
Globally, heterosexual transmission accounts for most HIV infections; in Australia, however, HIV infection remains predominantly a disease of men who have sex with men (MSM).
4
Most AIDS-defining illnesses occur when the CD4 T-lymphocyte count is below 200/μL (bacterial pneumonia and tuberculosis are exceptions).
5
Serious non-AIDS events that are not classically associated with HIV infection—such as cardiovascular disease, bone disease, renal disease and cognitive impairment—cause significant morbidity, may occur at higher CD4 cell counts and are possibly related to chronic inflammation.
6
Combination anti-retroviral therapy with well-tolerated and potent once-daily regimens dramatically reduces HIV mortality and morbidity, reduces the risk of HIV transmission from the infected individual to his or her partner and may decrease HIV transmission at a population level (treatment as prevention).
7
Close liaison between emergency department staff and the patient’s hospital or local doctor is vital for optimal management of HIV-infected patients.

Introduction

HIV medicine is a complex and specialized field and emergency physicians are not the usual primary care providers for people with HIV infection. However, the emergency department (ED) is often the first point of contact for patients presenting with acute HIV-related complications, whether or not they have already been diagnosed with HIV.

Emergency medicine physicians do not need to be HIV experts, but they should develop knowledge and skills in the following areas:

The natural history and clinical manifestations of HIV infection
The principles of HIV diagnosis, including the ability to engage patients in discussions about HIV testing and test results
The principles of early management of patients with common HIV-related disease syndromes
Knowledge of the antiretroviral agents in current use, including toxicity and drug interactions

The first cases of AIDS were recognized in the United States in 1981 and in Australia in 1982. The causative agent, human immunodeficiency virus (HIV), was discovered in 1984 and a diagnostic blood test was developed soon thereafter. In 1986, the first effective antiretroviral drug (azithrothymidine [AZT], later renamed zidovudine) became available. Since the late 1990s, the use of combination antiretroviral therapy (ART) has led to dramatic reductions in HIV-associated morbidity and mortality in resource-rich countries. Antiretroviral use is rapidly increasing in developing countries, with AIDS-related deaths having decreased by 43% since 2010. The world’s most affected region remains eastern and southern Africa. Worldwide 2.1 million infections were reported in 2015, adding up to a total of 36.7 million people living with HIV.

Epidemiology

The great majority of HIV infections globally arise as a result of heterosexual transmission. In developed countries, injecting drug use and men who have sex with men (MSM) account for a greater proportion of HIV infections, although the contribution of specific behaviours to overall transmission varies greatly within and between countries and over time.

In 2016 it was estimated that 26,444 people were living with HIV in Australia. The number of newly diagnosed cases remained stable between 2011 and 2016, with approximately 1000 new cases per year. Seventy-five percent of people infected with HIV report male-to-male sex, 20% become infected through heterosexual transmission and the rest occurred in other groups, including injecting drug users and recipients of contaminated blood or blood products. Women account for 9% of HIV-infected people and children less than 1%. Compared with some other countries, the prevalence of HIV infection in injecting drug users in Australia has remained low, in the order of 1% to 2%.

In 2016, an estimated 11% of all people living with HIV in Australia were unaware of their HIV status.

Pathogenesis

Once HIV infection becomes established, huge numbers of HIV virus particles are produced, chiefly in lymph nodes and other lymphoid tissue, accompanied by the daily turnover of up to 1 billion CD4 T lymphocytes. The number of CD4 cells falls secondary to mechanisms such as immune activation and direct infection of CD4 cells, resulting in reduced helper function for cell-mediated and humoral immunity.

HIV replication occurs at a relatively constant rate, producing a stable level of HIV in the blood; this can be measured with quantitative HIV RNA detection tests. The HIV viral load in combination with blood cell counts is used as a prognostic marker (because it is associated with the rate at which CD4 T lymphocytes are lost) and to monitor the efficacy of anti-retroviral therapy (ART).

The peripheral blood CD4 T-lymphocyte count is an accurate indicator of the degree of immunosuppression. The normal count is 500 to 1500 cells/μL; susceptibility to opportunistic infection and to most other serious HIV-related complications is greatest when the CD4 cell count is less than 200 cells/μL. In untreated patients the rate of decline in CD4 cells follow a skewed distribution, with progressive decline in CD4 cell count following HIV infection.

A wide variety of chronic medical conditions not previously associated with HIV infection—such as cardiovascular, bone and kidney disease, mild cognitive impairment and non-HIV related cancers—are more common in HIV-infected patients. Predisposition to these serious non-AIDS events results from a complex interplay between an ageing HIV-infected population, traditional risk factors, side effects of some antiretroviral agents and HIV infection itself. Chronic inflammation induced by HIV infection, which may persist despite effective ART, is thought to mediate some of the direct HIV effects.

Classification and natural history

HIV infection can be divided into the following stages:

Viral transmission
Acute HIV infection
- Seroconversion
Chronic HIV infection
- Asymptomatic
- Early symptomatic HIV infection
- AIDS, characterized by a CD4 cell count below 200 cells/μL or the presence of any AIDS-defining condition
- Advanced HIV infection characterized by a CD4 cell count below 50cells/μL

Patients are categorized as having AIDS when they develop an AIDS-defining condition regardless of the CD4 count, a CD4 cell count below 200 cells/μL , an HIV-related malignancy, a wasting syndrome or AIDS dementia complex.

Presentation

Patients with underlying HIV infection who present to the ED fall into three distinct groups. First, they may present with a manifestation of previously unrecognized HIV infection. To identify these patients, the physician must know who is potentially at risk of HIV infection (see ‘Epidemiology’, earlier) and be aware of the many different ways in which previously undiagnosed HIV infection may present. Prompt consideration of the possibility of HIV infection is important because the differential diagnosis of the presenting problem will broaden to encompass a variety of other conditions, some of which may be life threatening and require a different approach to initial investigation and treatment.

The second group includes those who are already known to be HIV-infected. Many of these patients will have been started on ART; serious HIV-related infections or malignancies are uncommon in this group, but ED presentations may be related to complications of therapy or to the chronic medical conditions associated with HIV infection discussed in the previous section. A smaller group of patients have developed resistance to or are intolerant of antiretroviral agents or decline to start or remain on treatment; these patients usually present with one of a limited number of classic HIV-related clinical syndromes, such as fever and cough or shortness of breath, diarrhoea, unexplained fever or neurological symptoms. The initial diagnostic and treatment approach is based on knowledge of the differential diagnosis for each of these syndromes.

Finally, there will be patients whose ED presentation is not related to an HIV complication at all but who have clinically silent, ‘incidental’ HIV infection. Readily identifiable groups who may be in this category are patients with a sexually transmitted infection (STI) and those with hepatitis B or hepatitis C infection. Otherwise a brief history including a sexual history is required to elicit HIV risk factors. Presentation of these patients to the ED offers an important opportunity to explore HIV risk factors and to discuss the benefits of early HIV diagnosis and the desirability of HIV testing.

Previously undiagnosed HIV infection

Acute seroconversion illness ( Box 9.7.1 )

The proportion of patients suffering from symptoms of acute infection varies greatly and 10% to 60% patients do not experience any symptoms at all. For those patients suffering from acute retroviral syndrome, the symptom duration and severity may vary widely. The highest frequency of symptoms and signs is observed just prior to peak viraemia, usually 2 weeks after the initial detection of viral RNA. The most common features are fever, fatigue, myalgia, rash, headache, lymphadenopathy and/or diarrhoea. Prolonged duration of any of these and the presence of mucocutaneous ulcers are suggestive of acute retroviral syndrome. The diagnosis is often missed at this stage; patients may be thought to have a ‘viral illness’, such as infectious mononucleosis or, if a patient develops a complication, more common causes (e.g. herpes simplex virus in a patient with encephalitis) and not HIV are considered.

Chronic HIV Infection

Asymptomatic infection

People are generally healthy during this phase. Thrombocytopaenia may occur; therefore HIV infection should be considered in appropriate patients with idiopathic thrombocytopenia.

Early symptomatic human immunodeficiency virus infection

This is a phase when previously undiagnosed HIV-infected patients often present with HIV-related conditions, but the clues may not be recognized as such and the underlying diagnosis can be missed. Manifestations that will alert the astute clinician include the following:

Minor infections: shingles, severe or very frequent orolabial or genital herpes, oral thrush
Skin conditions: extensive seborrhoeic dermatitis, worsening psoriasis
Constitutional symptoms: fever, weight loss, diarrhoea
Generalized lymphadenopathy
More serious complications: bacterial pneumonia (especially recurrent), tuberculosis and, rarely, Kaposi sarcoma or non-Hodgkin lymphoma

AIDS characterized by a CD4 cell count below 200 cells/μL or AIDS-defining condition

It is often not appreciated that patients may remain completely well during the early and intermediate stages of HIV infection and present only when they develop a serious HIV-related complication, such as an opportunistic infection. The ED may be the first point of medical care for such patients. If the history reveals risk factors for HIV infection, HIV testing can be performed and initial investigations directed at specific HIV-related complications. However, if the patient does not volunteer this information, is not specifically asked about HIV risk factors or does not belong to a ‘conventional’ HIV risk group, diagnosis of the presenting illness and the underlying HIV infection is often delayed.

The following clinical situations (discussed in more detail in the following section) should prompt consideration of the possibility of underlying HIV infection:

Diffuse bilateral pulmonary infiltrates (as a manifestation of Pneumocystis jiroveci pneumonia [PJP]): This is the commonest serious opportunistic infection in patients with previously undiagnosed HIV infection. It is often misdiagnosed as atypical pneumonia, leading to incorrect initial treatment with a macrolide agent or doxycycline.
Ring-enhancing space-occupying cerebral lesion: In non–HIV-positive patients, the usual cause is a tumour or bacterial brain abscess, and brain biopsy is required. In the setting of HIV infection, cerebral toxoplasmosis is the most likely diagnosis and brain biopsy can usually be avoided.
Tuberculosis: Although the overlap between those at risk for HIV and tuberculosis is not as great in Australia as in resource-poor countries with a high HIV burden, all patients with tuberculosis should be encouraged to undergo HIV testing after appropriate counselling.
Kaposi sarcoma: Well-developed lesions (purple, oval and nodular) are easy to recognize, but early lesions are often non-descript (brown or pink and flat) and biopsy may be required for diagnosis.
Other presentations: Unexplained cytopaenias (anaemia or pancytopenia) and other AIDS-defining conditions such as non-Hodgkin lymphoma, cryptococcal meningitis, chronic cryptosporidial diarrhoea or AIDS dementia complex (manifesting as impaired cognition and motor performance) are occasionally the first manifestation of previously unsuspected HIV infection.

Previously diagnosed HIV infection

Patients with known HIV infection are less likely to present with the classic AIDS-related clinical syndromes indicative of advanced immunodeficiency. However, previously diagnosed patients may fail ART or elect not to start or continue treatment and are still susceptible to AIDS-defining conditions. (Otherwise these presentations involve patients with previously unrecognized HIV infection, as discussed in the preceding section.) Patients with known HIV infection may also present with complications of ART, with chronic medical conditions not associated with HIV and of course with an acute problem not related to HIV at all.

Cough, shortness of breath, fever

Respiratory pathogens are listed in Box 9.7.2 . The most important issue is to decide whether the patient has PJP or not, because this complication is common and potentially serious. Tuberculosis must also be considered because of the need to place the patient in respiratory isolation.

PJP (strongly suspected in patients with CD4 cell count <200 cells/μL): The presentation is subacute or chronic, with a non-productive cough, dyspnoea, fever and chest tightness. Physical examination may reveal fever, tachypnoea and reduced chest expansion, but chest auscultation is often normal. PJP is unlikely in patients taking regular co-trimoxazole (a trimethoprim/sulphamethoxazole combination).
Bacterial pneumonia: Patients usually present with a short history, a productive cough and sometimes pleuritic chest pain. Physical examination may be normal or reveal signs of consolidation, a pleural rub or pleural effusion.
Patients who are immunosuppressed secondary to HIV have a high incidence of invasive streptococcal infection, although the availability of multi-valent pneumococcal vaccines has helped to decrease the incidence of these infections.
Tuberculosis: The clinical features vary according to the degree of immunosuppression. Patients with otherwise asymptomatic HIV infection usually present with typical symptoms and signs of tuberculosis (chronic cough, haemoptysis, fever and weight loss). However, in late-stage HIV infection, atypical manifestations such as disseminated disease are common and diagnosis is more difficult.

Box 9.7.1

Manifestations of primary HIV infection

Common (present in >30% of patients)	Less common	Complications
Fever Rash Myalgia/arthralgia Headache Pharyngitis Cervical lymphadenopathy Mouth ulcers	Diarrhoea Generalized lymphadenopathy Painful swallowing Abdominal pain Cough Photophobia Tonsillitis	Aseptic meningitis Guillain-Barré syndrome Encephalitis Interstitial pneumonitis Rhabdomyolysis Haemophagocytic syndrome

Box 9.7.2

Respiratory complications in HIV-infected patients

Common	Uncommon
Pneumocystis jiroveci pneumonia (PJP) Bacterial pneumonia: Streptococcus pneumoniae Haemophilus influenzae Bronchitis	Infectious: Tuberculosis Atypical mycobacteria Aspergillus pneumonia Other infectious: Rhodococcus equi , cytomegalovirus (CMV) Non-infectious: Pulmonary Kaposi sarcoma Lymphoma

Investigations

If the CD4 cell count is above 200 cells/μL, most patients can be managed as if they did not have HIV infection. Investigations required for patients with suspected bacterial pneumonia or tuberculosis include a chest x-ray, full blood examination, sputum examination and blood cultures.

If the CD4 cell count is below 200 cells/μL, investigation is almost always indicated. Its extent will be guided by the patient’s condition and the likely diagnostic possibilities.

Investigations may include some or all of the following:

Chest x-ray
Blood cultures
Sputum Gram stain, culture and acid-fast bacillus (AFB) smear and culture
Induced sputum for detection (by microscopy or polymerase chain reaction [PCR]) of PJP
Bronchoscopy, usually during inpatient admission.

A high index of suspicion for tuberculosis must be maintained; the diagnosis is generally suggested by one or more suggestive epidemiological, clinical or radiological features.

Management

Any person with suspected pulmonary tuberculosis must be placed in respiratory isolation until the diagnosis is excluded. Otherwise, on the basis of the initial diagnostic evaluation, patients can be categorized and management can proceed as follows:

Significant infection unlikely: no treatment.
Possible PJP: empirical PJP therapy with co-trimoxazole, and corticosteroids if saturation levels are below 93% at rest on room air oxygen.
Possible bacterial pneumonia:
Non-severe, outpatient—treat as for community-acquired pneumonia in immunocompetent patient.
Non-severe, inpatient—treat as for community-acquired pneumonia in immunocompetent patient.
Severe—consider community-acquired pneumonia regimens plus HIV-related opportunistic infections.
Possible tuberculosis—admission and respiratory isolation; treatment with isoniazid, rifampicin, pyrazinamide and ethambutol according to local guidelines if diagnosis confirmed; empirical therapy is sometimes necessary depending on clinical circumstances (e.g. suspected coexisting tuberculous meningitis).

Focal neurological signs, convulsions or altered conscious state

These features generally indicate the presence of an intracerebral space-occupying lesion, the most common causes of which are as follows:

Cerebral toxoplasmosis: This infection occurs when the CD4 cell count is below 200cells/μL. The specific focal features depend on the site of the usually multiple lesions and may include hemiparesis, visual field defects, personality change and/or cerebellar signs.
Primary intracerebral lymphoma: This complication occurs with advanced HIV infection (CD4 cell count usually below 500 cells/μL) and manifested in 2% to 3% of AIDS patients prior to the development of effective ART. It is associated with Epstein-Barr virus (EBV) infection. Clinical presentation is indistinguishable from that of cerebral toxoplasmosis.
Progressive multifocal leucoencephalopathy: Caused by JC virus (a polyomavirus). Patients present with cognitive decline or focal signs. Seizures are relatively uncommon. Differentiation from cerebral toxoplasmosis and primary cerebral lymphoma requires computed tomography (CT) or magnetic resonance imaging (MRI) (see later).

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