Human Immunodeficiency Virus Infection

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175 Human Immunodeficiency Virus Infection

In 1981, the first report of Pneumocystis (carinii) jiroveci pneumonia (PCP), in 5 healthy young men, heralded the arrival of a previously unknown pathogen and the disease it caused, later identified as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Since then, the infection has spread globally and has led to the untimely deaths of more than 25 million people. In the United States alone, more than 1.1 million people are estimated to be currently living with HIV/AIDS, and more than 50,000 new infections occur each year. Many of those infected, estimated to be more than 20%, may be unaware of their own HIV infection.

Despite some early advances in decreasing the yearly incidence of new infections, progress appears to have stalled. In certain subpopulations, the prevalence of HIV infection rivals that of some sub-Saharan African countries, such as men who have sex with men in New York City and black men in Washington, D.C. Injection drug users remain a high-risk group.

The mainstay of transmission of HIV infection is sexual exposure. The sharing of needles for illicit drug use also leads to transmission of HIV. An HIV-infected mother has approximately a 30% chance of passing the virus to her newborn, but with treatment, the risk plummets to less than 1%. Health care workers have a less than 0.3% chance of becoming infected with HIV following an accidental stick with a contaminated needle. Only in rare cases is HIV now transmitted through infected blood products (estimated to be less than 1 transmission per 500,000 blood transfusions) (Table 175.1).

Table 175.1 Risk of Human Immunodeficiency Virus Infection

ROUTE OF TRANSMISSION PER 10,000 EXPOSURES PERCENTAGE OR INCIDENCE
Transfusion of contaminated blood 9000 Almost 100%
Transfusion of blood after screening 1/500,000
Mother-to-child without treatment 3000 30%
Mother-to-child with treatment <0.01%
Needle stick in health care worker 30 0.3%
Unprotected receptive penile-vaginal intercourse 10
Unprotected insertive anal intercourse 6 0.01-1.0%
Unprotected insertive vaginal intercourse 5 0.01-1.0%
Unprotected receptive penile-vaginal intercourse with genital ulcers 100 0.1-10%
Unprotected receptive oral intercourse 1
Unprotected insertive oral intercourse 0.5

The HIV virions enter the host and primarily target the lymphocytes, particularly a subset of T lymphocytes known as CD4 cells. The virus establishes itself within the cells, where it prepares strands of DNA from its own viral RNA and the cells’ own enzyme reverse transcriptase. The new viral DNA becomes integrated within the lymphocytes’ DNA, and new virions are produced. The new virions are released from the host cell by budding and are free to invade other uninfected cells.

Initially, viral replication goes unchecked, and the high level of viremia may lead to symptoms such as fever, rash, pharyngitis, and enlarged lymph nodes. This stage is a transient illness, lasting days to several weeks, and has been termed acute HIV infection, or acute retroviral syndrome.

The immune system eventually responds to the viremia and suppresses viral replication. The viral load diminishes, and the symptoms of the acute infection resolve. Low-grade viral production continues at a steady state, and the host and virus reach a balance of viral suppression and continued viral production. This chronic steady state may be maintained for years until the immune system eventually is overwhelmed.

Infection with HIV is a progressive disease. Following years of viral replication, and eventual destruction of CD4 cells, the immune system begins to fail. During the chronic phase of infection, patients have a predictable decline of approximately 70 CD4 cells/µL/year. When the CD4 count approaches 200 cells/µL (from a normal level of approximately 1000 cells/µL), opportunistic infections (e.g., PCP, Kaposi sarcoma, pulmonary tuberculosis) begin to appear. When the CD4 cell count falls to less than 50 cells/µL, immunosuppression is profound.

Testing

The detection of HIV-specific antibodies in serum or plasma establishes the diagnosis of HIV infection. Tests of HIV antibodies are highly sensitive and specific. The enzyme-linked immunosorbent assay (ELISA) is the most commonly used screening test for HIV because of its high sensitivity and rapid results. All positive test results should be confirmed by Western blot. The Western blot test uses electrophoresis to separate HIV proteins, which produce a colored band after reacting with specific antibodies found in a sample of blood. It is the most commonly used confirmatory test and is considered the “gold standard.”

Following the initial HIV infection, antibody production occurs at such low levels that antibodies are undetected by most assays. This window period, in which HIV antibody testing leads to false-negative results, lasts approximately 4 weeks. In this setting, testing directly for the viral antigen p24 or polymerase chain reaction (PCR) testing for viral RNA may be performed. The U.S. Food and Drug Administration (FDA) has approved a newer test that detects both p24 antigen and antibodies to HIV. This highly sensitive assay, the ARCHITECHT HIV Antigen/Antibody (Ag/Ab) Combo, will be instrumental in detecting early stages of infection.

Monitoring Infection and Treatment

Monitoring the progression of infection with HIV has been likened to a runaway train on railroad tracks that lead to the edge of a cliff. The CD4 cell count is analogous to the distance between the train and the cliff, and the viral load is analogous to the speed of the train.

Close monitoring of the level of viremia and of the CD4 cell counts is crucial in the management of the HIV-infected patient. PCR testing quantitatively measures the viral RNA in copies per milliliter of plasma, the viral load. Untreated patients typically have viral loads of up to 1,000,000 copies/mL of HIV RNA. One goal of antiretroviral therapy is to decrease the viral load sufficiently to be undetectable, as occurs when fewer than 5 to 50 copies/mL of HIV RNA are present. The CD4 cell counts provide prognostic information. Patients with CD4 cell counts higher than 200 cells/µL rarely develop opportunistic infections, and those with counts higher than 50 cells/µL rarely die of HIV/AIDS.

Viral resistance to antiretroviral medications is an emerging phenomenon that may require alteration of a particular antiretroviral regimen. Two types of tests measure HIV resistance. The first is genotype testing, in which the sequences of the relevant viral genes are determined. The sequences reveal the presence or absence of mutations associated with antiretroviral resistance. Second, phenotypic tests excise relevant viral genes and insert them into a standard test virus. The test virus is then exposed to various antiretroviral medications to determine resistance.

Acute Infection

Acute HIV infection, also termed acute retroviral syndrome or primary HIV infection, is a self-limited stage that develops in the first few weeks following initial infection. During this period, viral replication is rapid and ongoing, leading to high viral loads. The CD4 cell count may decrease transiently during the acute phase. The signs and symptoms are nonspecific and most commonly include fever and rash (Box 175.1). Approximately one third of patients are asymptomatic. The average duration of illness is 14 days, but this stage may last from a few days to more than 10 weeks.3

In time, the immune system recovers. CD8 cells proliferate, and the humoral immune system produces antibodies that lead to diminishing viremia. With the falling viral load, symptoms also subside. Testing for HIV-specific antibodies (e.g., ELISA) during the early phase often produces false-negative results because of the low levels of antibodies. Testing for viral p24 antigen and PCR testing of HIV RNA are other options.

As many as one half of all new HIV transmissions are estimated to occur from persons newly infected with HIV themselves. These people are likely to have extremely high viral loads, and many are unaware of their own HIV infection and therefore continue risky behaviors. The importance of establishing the diagnosis of acute HIV infection lies in early therapy for the individual and the decrease in transmission to others.

Current guidelines recommend antiretroviral therapy (ART) for symptomatic acute HIV infection. Early treatment decreases the viral load set-point, preserves immune function, suppresses the development of viral mutations, reduces transmission, and may slow the progression to AIDS.

Acute HIV infection is often not recognized in the primary care setting because the nonspecific symptoms resemble an influenza-like illness. When patients with febrile influenza-like illnesses are evaluated, clinicians need to consider inquiring about recent (past 2 to 6 weeks) high-risk behaviors. If suspicion of acute HIV infection arises, testing should include a plasma HIV RNA assay (viral load), or p24 antigen, in addition to HIV-specific antibody testing (ELISA). Consultation with an infectious disease specialist is warranted to arrange for further testing, to assist with initial ART, and to arrange a link to future care of the patient.

Opportunistic Infections

Opportunistic infections continue to be responsible for considerable morbidity and mortality in people infected with HIV. The introduction of ART has been profoundly beneficial in decreasing the number and severity of opportunistic infections. Unfortunately, not all HIV-infected people worldwide have access to ART, and resistance to ART continues to advance. The following sections discuss examples of opportunistic infections likely encountered in the ED.

Central Nervous System Infections

Pulmonary Infections

Pneumocystis pneumonia

Pneumocystis (carinii) jiroveci is the organism causing PCP. Despite a decline in the incidence of PCP as a result of ART and prophylaxis, many patients who are diagnosed with PCP are unaware of their underlying HIV infection. PCP is most likely to occur in patients with CD4 cell counts lower than 100 cells/µL.

Patients with PCP tend to experience a subacute illness with a dry cough, fever, and progressive dyspnea that worsens over the course of days to weeks. On physical examination, one may note tachycardia, tachypnea, and fine crackles on auscultation of the lungs. The patient may also have oropharyngeal candidiasis. Radiographs of the chest may be normal in the early stage of infection, but the common findings are bilateral and diffuse interstitial infiltrates.

The definitive diagnosis is by recovery of the organism from the lung. Expectorated sputum samples have a very low diagnostic yield and are not recommended. Bronchoalveolar lavage is the preferred method of obtaining clinical specimens. Many patients are treated empirically based on the clinical presentation, presence of hypoxia, and elevation of lactate dehydrogenase level to more than 500 mg/dL (a common but nonspecific finding in PCP). The drug of choice is trimethoprim/sulfamethoxazole, orally for mild to moderate disease and intravenously for more severe infection. Those patients with severe disease, as defined by a room air oxygen pressure of less than 70 mm Hg, should receive additional treatment with corticosteroids in the ED. The current recommendations are for a regimen of prednisone, 40 mg orally twice daily for 5 days, then 40 mg orally once daily day for 5 days, then 20 mg orally once daily for an additional 11 days.

Gastrointestinal Infections

Antiretroviral Therapy

The life expectancy of persons newly infected with HIV continues to increase because of advances in ART. Incredibly, most HIV-infected patients who are receiving ART will die of something other than AIDS. The goal of treatment is complete viral suppression to lower than detectable levels, to prevent viral replication and mutation that may lead to resistance. Additionally, viral suppression protects the immune system from eventual destruction. With the development of new ART, physicians increasingly design regimens that are long lasting and well tolerated, and they are more able to construct subsequent lines of therapy that can continue viral suppression. Advances in newer classes of drugs (e.g., integrase inhibitors, fusion inhibitors) offer the promise of more potency and fewer adverse effects. The development of fixed-dose combinations revolutionized the treatment of HIV by allowing fewer pills and less frequent dosing, thereby enhancing the tolerability of therapy. The combination pill containing efavirenz, emtricitabine, and tenofovir is dosed by one pill once a day.

Currently, 23 antiretrovirals are available (Box 175.2). The early initiation of ART can prevent the progressive destruction of the immune system that occurs even when a patient is asymptomatic and has been shown to reduce mortality markedly. Safety and tolerability of new ART regimens and increasing evidence of the detrimental effects of uncontrolled viremia led to changes in the latest management guidelines. The 2010 International AIDS Society-USA Panel revised recommendations for adults with HIV infection to include initiating ART for all asymptomatic patients with a CD4 cell count of up to 500/µL.4 Additionally, ART is recommended, regardless of CD4 cell count, for all symptomatic patients, as well as those who are pregnant, those with hepatitis B or C coinfection, patients with HIV-associated nephropathy, persons with active or high-risk coronary artery disease, persons more than 60 years old, patients with acute HIV infection, or persons with a high risk of HIV transmission.

Antiretroviral medications are primarily prescribed by specialists in the field and are given in various combinations to prevent the development of drug resistance. The recommendations include the combination of nucleoside and nucleotide analogue reverse transcriptase inhibitors (emtricitabine and tenofovir) with a non-nucleoside reverse-transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir/ritonavir), or the integrase inhibitor (raltegravir). The precise combination selected depends on the patient’s individual condition. The FDA approved six fixed-dose combination pills that greatly simplified therapy and enhanced adherence.

Adverse Effects

Investigators have estimated that approximately 25% of all patients will discontinue ART because of side effects. Adverse reactions may be mild to potentially life-threatening (Table 175.2). Distinguishing between these adverse effects and possible symptoms of infection with HIV or opportunistic pathogens is often difficult for clinicians. Emergency physicians must be familiar with the frequently encountered, and possibly deadly, adverse effects of ART.

Table 175.2 Adverse Effects of Antiretroviral Agents

AGENTS ADVERSE EFFECTS*
Nucleoside Reverse Transcriptase Inhibitors
Abacavir Rash
Hypersensitivity*
Didanosine Pancreatitis*
Peripheral neuropathy
Transaminitis
Emtricitabine Headache
Rash
Hyperpigmentation
Lamivudine Headache
Stavudine Peripheral neuropathy
Zidovudine Headache
Myalgias
Anemia (elevated mean corpuscular volume)
Non-nucleotide Analogue Reverse Transcriptase Inhibitors
Tenofovir Lactic acidosis*
Hepatitis
Renal insufficiency
Non-nucleoside reverse transcriptase inhibitors Rash
Delavirdine Severe rash*
Hepatitis
Fatigue
Efavirenz Hepatitis*
Severe rash
Central nervous system effects or abnormal dreams
Etravirine Elevation of liver function tests
Nevirapine Stevens-Johnson syndrome*
Severe rash*
Hepatitis*
Fever
Headache
Protease Inhibitors Dyslipidemia
Lipodystrophy
Hyperglycemia
Elevations of liver function tests
Atazanavir Jaundice
Darunavir Rash
Fosamprenavir Rash
Indinavir Nephrolithiasis
Lopinavir/ritonavir Taste perversion
Nelfinavir Enteritis
Ritonavir Taste perversion
Saquinavir Oral ulcers
Tipranavir Rash
Fusion Inhibitors
Enfuvirtide Injection site reactions
Neutropenia
Maraviroc Hepatitis
Myalgias or arthralgias
Integrase Inhibitor
Raltegravir Elevation of liver function tests
Rash

* Severe adverse effect warrants discontinuation of all antiretrovirals.

Common adverse effects are primarily gastrointestinal (e.g., nausea, vomiting, diarrhea). More severe reactions include lactic acidosis. Patients often present with nonspecific symptoms such as fatigue, shortness of breath, nausea, and weight loss, and laboratory testing confirms the diagnosis by demonstrating an elevated anion gap metabolic acidosis and a serum lactate level higher than 3 mmol/L. Treatment is supportive, with immediate discontinuation of ART. Hepatotoxicity with transaminitis is primarily associated with protease inhibitors and the non-nucleoside reverse transcriptase inhibitors and warrants discontinuation of ART. Abacavir may cause a hypersensitivity reaction, usually seen within the first 6 weeks of initiating therapy, characterized by fever, myalgia, malaise, nausea, vomiting, anorexia, and rash. Symptoms progressively worsen with continued administration. Treatment is again supportive, and abacavir must be permanently discontinued. Consultation with an infectious disease expert is prudent in the management of adverse effects of ART.

Prophylaxis Against Common Opportunistic Infection

Patients infected with HIV infection and who are severely immunosuppressed are at risk for many opportunistic infections. Long-term antimicrobial prophylaxis has been demonstrated to be beneficial in preventing several common opportunistic infections (Table 175.3).

Table 175.3 Prophylaxis Against Opportunistic Infections

OPPORTUNISTIC INFECTION INDICATION RECOMMENDED ANTIMICROBIAL
Pneumocystis pneumonia CD4 cell count < 200 cells/µL
or history of oropharyngeal candidiasis
TMP/SMX 1 DS/day PO
Toxoplasmosis CD4 cell count < 100 cells/µL TMP/SMX 1 DS/day PO
Disseminated
Mycobacterium avium complex
CD4 cell count < 50 cells/µL Azithromycin 1200 mg/wk PO

DS, double strength; PO, orally; TMP/SMX, trimethoprim-sulfamethoxazole.

Postexposure Prophylaxis

Occupational Exposure

Although the risk of occupational transmission of HIV to health care workers is quite small, it is not zero. Percutaneous exposure to blood from an HIV-infected patient carries an estimated risk of transmission of approximately 0.3%. Similar exposures to mucous membranes are associated with a 0.09% risk of transmission, and the risk of transmission following exposure to nonintact skin is even lower. The CDC provides recommendations for the management of health care workers exposed to HIV and for postexposure prophylaxis (PEP). These recommendations are based on the severity of the exposure and the viral load of the source patient (Box 175.3).5 Health care workers with low-risk exposures are recommended to take the basic two-drug regimens. A small-volume blood exposure to mucous membranes or nonintact skin from a source patient who is asymptomatic or who has a low viral load (<1500 RNA copies/mL) represents a low risk of infection (Box 175.4). Those with high-risk exposures are recommended to take the expanded three-drug regimen of PEP. Percutaneous exposure to a source patient with a high viral load is considered to carry a higher risk.

No PEP is recommended for any type of exposure if the source patient is HIV negative. Saliva, tears, nasal secretions, sputum, gastric fluids, urine, and feces are not infectious unless they are visibly bloody. All medications should be initiated as soon as possible, and all regimens should be continued for 28 days. Initiating PEP 72 hours after exposure is not effective, and it is generally not recommended. Available resources include a 24-hour telephone help line (PEPline: 888-448-4911) and online information from the National HIV/AIDS Clinicians’ Consultation Center at www.nccc.ucsf.edu.

Nonoccupational Exposure

In 2005, the CDC published recommendations for antiretroviral PEP following sexual exposure, injection drug use, or other nonoccupational exposure to HIV.6 A 28-day course of ART is now recommended for persons seeking care less than 72 hours after nonoccupational exposure to blood, genital secretions, or other potentially infectious bodily fluid from a source known to be HIV positive.

Nonoccupational PEP (nPEP) is not always effective, and antiretroviral medications may produce harmful adverse effects, so all persons should be evaluated on a case-by-case basis. For example, persons who engage in high-risk behaviors, resulting in frequent exposures to HIV and the use of multiple and repeated courses of antiretrovirals, should not take nPEP. They should instead be counseled on risk-reduction strategies. All persons should be tested for baseline HIV infection. Additionally, they should be evaluated for other sexually transmitted diseases because the presence of these diseases may increase the risk of transmission of HIV.

Substantial exposure risk is defined as exposure of vagina, eyes, rectum, mouth, or other mucous membranes, or nonintact skin, or percutaneous contact, with blood, semen, vaginal secretions, rectal secretions, breast milk, or any bodily fluid that is visibly contaminated with blood from a source that is HIV positive. Negligible exposure risk is defined as exposure of vagina, eyes, rectum, mouth, or other mucous membranes, or nonintact skin, or percutaneous contact, with urine, nasal secretions, saliva, sweat, or tears if not visibly contaminated with blood, regardless of the known or suspected HIV status of the source. If the source’s HIV status is unknown, the source should be tested, if possible. The first dose of nPEP may be given initially, and no further doses are given if the source is determined to be HIV negative. If the source’s HIV status cannot be determined and the person seeking care had a substantial risk exposure, consideration of the source patient’s risk of having HIV is warranted. High-risk populations include men who have sex with men, commercial sex workers, those who inject drugs, those with history of incarceration, persons from countries where the HIV seroprevalence is at least 1%, or sexual partners of persons at high risk. Perpetrators of sexual assault are considered to have a high risk for HIV. Substantial exposure to high-risk populations warrants nPEP (Box 175.5).

Once the decision has been made to initiate nPEP, ART should be administered promptly. The basic regimens recommended for occupational PEP are also recommended for nPEP (see Box 175.4).7 The expanded regimens are reserved for patients exposed to a source population in which background resistance of HIV to ART is high.

Persons who are given nPEP must be counseled on the potential adverse effects, in particular nausea, vomiting, and diarrhea, and must be offered symptomatic therapy such as antiemetics or antimotility drugs. All persons receiving nPEP should have prompt follow-up care provided by their primary care practitioners or an infectious disease specialist.

Prevention of HIV Infection

Exciting data have revealed fundamentally new, effective approaches to prevent HIV transmission. The Center for the AIDS Program of Research in South Africa (CAPRISA) study demonstrated the effectiveness and safety of a 1% vaginal gel formulation of tenofovir for the prevention of HIV acquisition in women.8 A double-blind, randomized controlled trial comparing tenofovir gel with placebo demonstrated a reduction in risk of HIV transmission by more than one half. This microbicide gel allows women around the world to play a greater role in HIV prevention when compared with relying on their partners to use condoms.

The second landmark report was the Preexposure Prophylaxis Initiative (iPreEx) trial.9 This study, conducted in six countries, included 2499 HIV-negative men who had sex with men to evaluate whether antiretroviral medications could prevent the transmission of HIV. A once-daily antiretroviral combination pill of emtricitabine and tenofovir was compared with placebo. The participants were followed for an average of 14 months. The antiretroviral group demonstrated a 44% reduction in the incidence of HIV compared with the placebo group, and a subset of participants with enhanced compliance had an even greater risk reduction of 73%. This trial clearly showed that preexposure prophylaxis is generally safe, well tolerated, and effective. Together, these two reports demonstrate significant advances in the prevention of HIV transmission.

References

1 Greenwald JL, Burstein GR, Pincus J, Branson B. A rapid review of rapid HIV antibody tests. Curr Infect Dis Rep. 2006;8:125–131.

2 Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Morb Mortal Wkly Rep. 2006;55:1–17.

3 Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998;339:33–39.

4 Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA Panel. JAMA. 2010;304:321–333.

5 Panlilio AL, Cardo DM, Grohskopf LA, et al. Updated U.S. Public Health Services guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep. 2005;54:1–17.

6 Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States. MMWR Morb Mortal Wkly Rep. 2005;54:1–20.

7 Landovitz RJ, Currier JS. Postexposure prophylaxis for HIV infection. N Engl J Med. 2009;361:1768–1775.

8 Karim QA, Karim SSA, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science Express on behalf of the CAPRISA 004 Trial Group http://www.sciencemag.org/cgi/rapidpdf/science.1193748.pdf, 2010.

9 Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–2599.