Human immunodeficiency virus (HIV) is a retrovirus that infects primarily CD4+ T-helper cells. Depletion of these cells causes progressive immunologic decline. When CD4 T-cell counts fall below 200 cells/mm³ or opportunistic infections occur, an infected patient is described as having the acquired immune deficiency syndrome (AIDS).

Disease caused by the virus was first described in 1981 when an epidemic of Pneumocystis carinii pneumonia (PCP) was noted in homosexual men.¹ In 1984, HIV was identified as the causative agent of AIDS. Subsequently, two genetic types of HIV were identified. The predominant type worldwide is HIV-type 1 (HIV-1). HIV-1 is further subdivided into subtypes (also called clades), designated A through K (collectively referred to as group M), N and O. More than 98% of HIV-1 infections in the United States are due to subtype B.² HIV-type 2 (HIV-2) is found in West Africa, particularly Guinea-Bissau, Gambia, and Senegal, as well as in France, Portugal, Angola, and Mozambique. Disease caused by HIV-2 appears to be less readily transmissible and results in slower disease progression than HIV-1.³

More than 400,000 people were reported to be living with HIV infection or AIDS in the United States in December 2000. In actuality, however, more than 800,000 to 900,000 are estimated to have been HIV-infected at that time, because many states do not require reporting of HIV-infected persons and many persons are unaware of their HIV status. Therefore, more precise determinations of actual prevalence remain elusive. Among those diagnosed with AIDS in 2000, three quarters were males. Forty-seven percent were black non-Hispanic, 32% were white non-Hispanic, and 19% were Hispanic. Fewer than 1% of cases were in children under age 13. Among males with AIDS diagnosed in 1999, the predominant HIV exposure was male-to-male sex in 53%, while 26% reported a history of injecting-drug use. Sixty-two percent of females diagnosed with AIDS in 1999 identified heterosexual sex as their HIV exposure, and 35% had injecting-drug use as a risk factor. Once a predominant mode of transmission, receipt of blood products accounted for only 1.6% of cases of AIDS in 1999.⁴

The magnitude of the global HIV/AIDS epidemic vastly exceeds that in the United States. At the end of 2001, more than 40 million people were estimated to be living with HIV/AIDS, and more than 20 million had already died from AIDS. Nearly three quarters of those with the disease are living in sub-Saharan Africa, where access to antiretroviral therapy is limited.⁵

The HIV viruses belong to the lentivirus subfamily of the RNA retroviruses. Like most retroviruses, the HIV genome consists of three structural genes: gag, pol, and env. The gag gene codes for viral capsid proteins, env for the viral envelope proteins, and pol for the proteins responsible for viral replication, including the RNA-dependent DNA polymerase known as reverse transcriptase. In addition, several other regulatory genes are present, including nef, rev, and tat.

Most commonly, transmission of the virus occurs after a breach in the integument or mucous membranes. HIV infection occurs when the envelope subunit gp120 binds the human CD4 T-cell receptor found primarily on lymphocytes and monocyte-derived macrophages. In addition, binding also requires the presence on the host cell of the chemokine receptor CCR5 or CXCR4. The viral envelope then fuses with the host cell, allowing release of the viral core into the host cell. Viral DNA is synthesized by reverse transcriptase and incorporated into the host genome by the protein integrase. Once the viral gene products are transcribed and assembled, the HIV protease mediates packaging of new virions for release into serum to propagate the infection.⁶

Over time, infected persons have a progressive loss of CD4+ lymphocytes, although in the early stages of infection, this is not associated with increased immunosuppression. The rate of CD4 cell loss is variable and depends on viral and host factors. On average, infected persons lose 40 to 80 CD4 cells/mm³ per year.⁷ A subset of individuals will progress rapidly, and 5% of infected persons, known as long-term nonprogressors, will have little or no progression of clinical disease or decline in CD4 counts over 10 years even without antiretroviral therapy.⁸

Transmission of the virus occurs through exposure to infected body fluids, including blood, semen, and vaginal fluid. The most common modes of transmission are sexual contact (male-male or heterosexual sex), parenteral exposure to blood and blood products, and vertical transmission during pregnancy. The magnitude of risk depends on the exposure. For example, the risk of HIV transmission from a known HIV-positive source from receptive anal intercourse is 0.1% to 0.3%, while receptive vaginal intercourse carries a risk per episode of 0.08% to 0.2%. A percutaneous exposure such as a needlestick injury or injecting-drug use results in transmission 0.4% or 0.67% of the time, respectively.⁹ The risk of vertical transmission from mother to fetus without any preventive therapy is approximately 25%.¹⁰ The efficiency of transmission increases with greater degrees of viremia in the source patient and the presence of concurrent sexually transmitted diseases.

Acute HIV Infection
In an estimated 40% to 90 % of individuals, HIV seroconversion is associated with a clinical syndrome known as acute/primary HIV infection or the acute retroviral syndrome. In one prospective study, among those with symptoms at the time of seroconversion, 95% sought medical care. Nevertheless, acute HIV infection is rarely diagnosed, partly because the symptoms are protean. The onset of illness is between 2 and 6 weeks after viral transmission and is thought to correlate with peak viremia, often in excess of 1 million viral copies/mL. Fever (mean 38.9°C), rash, lymphadenopathy, and nonexudative pharyngitis are each present in at least 70% of individuals (Table 1). Most often the rash is reminiscent of a viral exanthem with erythematous maculopapular lesions on the face and trunk, although many types of lesions have been described. Headache with or without cerebrospinal fluid pleocytosis, myalgias, and gastrointestinal symptoms are also common. Although present in only 5% to 20% of patients, oral or genital ulcers can be an important diagnostic clue. Laboratory abnormalities, specifically leukopenia, thrombocytopenia, and elevated transaminases, are not uncommon. Opportunistic infections such as mucocutaneous candidiasis and PCP may present during acute HIV infection as a result of transient but dramatic CD4 cell count depletion due to the high level of viremia.

The symptoms of acute HIV infection are self-limited and most likely correlate with viremia. After reaching high levels, the viral load declines to a steady state or set point, and the CD4 count recovers. HIV-1-specific cytotoxic T lymphocytes are present in high titer and appear to play an important role in controlling viral replication. The magnitude of the viral set point and the severity of initial symptoms predict disease progression. Some experts advocate early antiretroviral treatment, which may alter the viral set point and slow progression of disease. Patients treated acutely appear to have a more robust HIV-specific cell-mediated immune response. Recognition of this syndrome has obvious implications for public health but may also have an impact on the individual's disease course.¹¹ Diagnosis will be discussed below.

Chronic HIV Infection
A variety of historical details, findings on physical examination, and laboratory abnormalities should prompt testing to identify individuals with established HIV infection. As expected, these findings are more prominent in patients with more advanced disease. Frequently, the initial diagnosis of HIV infection is made when the patient develops an AIDS-indicator condition (Table 2).¹² However, the astute clinician can often detect signs and symptoms of HIV infection earlier in the course of disease, allowing access to appropriate therapy and prophylaxis before significant illness develops.

Physicians must conduct a thorough, nonjudgmental assessment of risk factors for HIV infection. Testing should be offered to individuals with a history of injecting-drug use, sexually transmitted diseases including human papillomavirus, hemophilia, and receipt of blood products between 1977 and 1985. Men who have had sex with men, sex workers, and heterosexual persons with multiple partners are also at high risk, as are the sexual partners of high-risk or HIV-infected individuals. Mental illness and incarceration may serve as markers for high-risk behavior, as does a history of hepatitis B or C infection. Persons who consider themselves at risk should receive testing even if risk behaviors are not disclosed.

A history of certain illnesses can also be suggestive of HIV infection (Table 2). Infections such as active tuberculosis, recurrent community-acquired pneumonia, esophageal candidiasis, and either multidermatomal herpes zoster or zoster in younger adults should lead to HIV testing. Neoplastic diseases such as B-cell lymphoma, severe anal or cervical dysplasia, or invasive carcinoma and Kaposi's sarcoma are indications for HIV testing, as is idiopathic dilated cardiomyopathy. The evaluation of fever of unknown origin or unexplained weight loss should always include an HIV test, even in elderly patients without identified risk factors.

Various findings on physical examination may suggest coexisting HIV infection. Examination of the skin can be particularly revealing. Seborrheic dermatitis or molluscum contagiosum are common in early disease, as is psoriasis. Oral candidiasis and oral hairy leukoplakia can be seen, typically with CD4 counts less than 500 cells/mm³. Generalized lymphadenopathy is common. Recurrent or severe lesions of herpes simplex virus may be indicative of underlying HIV infection. Neurologic findings such as unexplained peripheral neuropathy or dementia are suggestive.

On laboratory evaluation, idiopathic thrombocytopenia, unexplained anemia, neutropenia, and/or leukopenia are frequent early clues to underlying HIV infection.

Since the recognition that HIV is the agent causing AIDS, many tests have been developed to aid in establishing the diagnosis of HIV infection and evaluating the stage of infection. Only a few have application today for routine use.

Serologic Tests
The principal tests for diagnosis of HIV-1 infection are the HIV enzyme-linked immunosorbent assay (EIA, ELISA) and the confirmatory Western blot. Both detect host antibodies to the HIV virus. The EIA is the initial screening test and has a sensitivity and specificity > 99%. A false-negative EIA result occurs most commonly when the test is performed in a newly infected patient before an antibody response has developed ( the so-called window period). Most patients will have a positive EIA finding 10 to 14 days after infection, although seroconversion may be delayed in some. False-negative results occur rarely in patients with late-stage disease and in those with subtype N or O HIV-1 infection. False-positive results occur in a variety of settings, including in patients with autoimmune diseases, multiparity, and liver disease as well as in recipients of multiple transfusions, hemodialysis, and vaccinations.¹³ An isolated positive EIA finding should never be considered evidence of HIV infection, and practitioners should counsel patients accordingly.

The confirmatory study for a persistently positive EIA finding is the Western blot, which detects antibodies to specific HIV proteins. A positive study is defined as one in which bands to two of the following three proteins are present: the envelope proteins gp41 and gp120/160 and the viral capsid protein p24. A negative Western blot has no positive bands, but a study with any positive bands that do not meet the above criteria is considered indeterminate. Four percent to 20% of patients with persistently positive EIAs have indeterminate Western blot findings. Indeterminate findings may occur during the so-called "window period" between infection and seroconversion. Alternatively, other conditions such as autoimmune disease can lead to an indeterminate study. Western blots have a reported specificity of 97.8%; therefore, false-positive results can occur. Patients with both false-positive EIA and false-positive Western blot results are rare (6 to 7 per 1 million tests).¹³

The diagnosis of HIV-2 infection requires an EIA that will detect HIV-2 antibodies, followed by an HIV-2-specific Western blot. Many currently available HIV EIAs will detect antibodies to HIV-1 or HIV-2; however, HIV-2-specific EIAs are also available.

Newer diagnostic tests using EIA or immunofluorescence technology are now available for use in specific circumstances. Most popular are the rapid testing systems, which allow the assay to be run in less than 30 minutes. These are particularly beneficial in the delivery room, emergency room, and after occupational exposures. The only FDA-approved kit at present is the SUDS (Single Use Diagnostic System; Murex, Norcross, GA) although others, including rapid assays of saliva, may be available soon. In addition, home tests are available that allow patients to perform a fingerstick test and send a blood sample anonymously for testing (Home Access Express Test, Home Access Health Corp., Hoffman Estates, IL). The OraSure (Epitope Co., Beaverton, OR) kit allows for testing of oral mucosa transudate, and the Calypte kit (Calypte Inc., Alameda, CA) tests for HIV antibodies in urine. Vaginal-secretion testing kits are under development.¹³ Test counseling is necessary regardless of the methodology used.

As with all diagnostic tests, the positive predictive value depends on the rate of disease in the population being screened. In low-prevalence populations, the likelihood that a positive EIA represents a false-positive result may exceed the likelihood of the test's indicating true HIV infection.

Quantitative HIV Testing
Quantitative plasma HIV RNA (viral load) testing is most commonly used to measure response to antiviral therapy or to predict disease progression. Several methods of measuring viral load are commercially available including viral RNA quantification by the polymerase chain reaction (PCR), branched-chain DNA assays, and nucleic acid sequence-based amplification. At present, RNA PCR is most commonly utilized. This test should not be used for diagnosis of HIV infection unless acute HIV infection is a consideration. HIV-infected individuals can have undetectable viral loads in the absence of antiviral therapy, and the false-positive rate approaches 3%. When the practitioner is concerned about acute HIV infection with a symptomatic patient and the EIA/Western blot findings are negative or indeterminate, viral load testing can be helpful. With initial viremia, before development of an immunologic response to the virus, the viral load is extremely high, often greater than 100,000 copies/mL. Low viral loads (< 15,000 copies/mL) with negative serologic studies may represent a false-positive RNA PCR result and should be repeated.¹³ Qualitative measurements of proviral DNA can also be useful for detection of viremia before seroconversion.

Measurements of p24 antigenemia have also been used to detect HIV infection before seroconversion. On average, however, HIV DNA or RNA can be detected 2 to 3 days earlier than the p24 antigen. As a result, viral load testing has become the preferred method of diagnosis for acute HIV infection. Studies of p24 antigen can be useful to help clarify confusing serologic or quantitative viral load results.

In summary, serologic testing is the gold standard for diagnosing HIV infection and should be performed on all patients in whom HIV infection is suspected. Viral load testing has no role in the diagnosis of established HIV infection. When suspicion of acute HIV infection is present, viral load testing can be performed in addition to serologic studies. Negative serologic studies in the setting of a strongly positive viral load (> 15,000 copies/mL) suggest acute HIV infection. These patients should be urgently referred to an HIV specialist; however, seroconversion must be documented as well in the ensuing weeks to months. Indeterminate Western blot findings can present challenging management issues. At a minimum, the study should be repeated 6 months after the initial result to clarify whether the indeterminate findings were the result of ongoing seroconversion.

Appropriate treatment of the HIV-infected individual requires much more than consideration of antiretroviral therapy. The initial evaluation of an HIV-infected patient should include a careful medical and social history, a medication history including alternative and herbal supplements, and a thorough physical examination. The practitioner should explore the patient's knowledge of HIV, understanding of the course of disease, emotional well-being, and the presence of support systems. A discussion of safer sex practices and contraception is vital. Notification of sex partners should be discussed. Identification of a durable power of attorney and discussion of advanced directives is valuable early in disease.

Several baseline laboratory studies aid in establishing a treatment plan for the patient, choosing agents for antiretroviral therapy, and guiding prophylaxis (Table 3). These studies include a complete blood cell count with differential and platelet counts, electrolytes, BUN and creatinine, transaminases and alkaline phosphatase, rapid plasma reagin or VDRL to assess for syphilis, Toxoplasma gondii IgG serology to assess past exposure, hepatitis B and C serologies, G6PD level, and a CD4 count and HIV viral load measurement. Many practitioners favor cytomegalovirus IgG and hepatitis A IgG serologies as well. A purified protein derivative (PPD) test must be placed if not done in the past year, and assessment of exposure to any individuals with active tuberculosis must be performed. An anergy panel is not necessary. Women should have a Pap smear performed every 6 months until two consecutive smears are negative, then annually. Women with abnormal Pap smears should be referred for colposcopy. Some authorities recommend that patients receive a baseline chest radiograph.

Annual ophthalmologic and dental visits are recommended. Consultation with a nutritionist experienced in HIV care and a social worker are beneficial.

Preventive Treatment
Preventive care is essential to treating the HIV-infected patient. Some infections can be minimized by avoiding uncooked and undercooked foods such as seafood, eggs, and meats; abstaining from drinking lake and river water; avoiding contact with litter boxes and animals with diarrhea; and institution of careful hand washing. The patient's vaccination history should be carefully reviewed. All patients should receive the pneumococcal vaccine, updated every 3 to 6 years. The influenza vaccine is recommended, as is hepatitis B vaccination if the patient is seronegative. While hepatitis A vaccination is indicated if the patient has existing hepatitis B or C, most practitioners favor vaccinating all seronegative individuals. Tetanus boosters are indicated every 10 years. At present, live vaccines are not recommended in patients with advanced disease. The safety of these vaccines, which include varicella, measles-mumps-rubella, and yellow fever, early in disease is unknown and can be considered individually. The inactivated vaccines for typhoid (Typhim Vi capsular polysaccharide vaccine (ViCPS)) and polio should be administered when required rather than the live vaccines (See 2001 USPHS/IDSA guidelines).

Patients with advanced HIV disease require prophylaxis to prevent opportunistic infections. At CD4 counts less than 200 cells/mm³ or CD4% < 14, prophylaxis against PCP should be initiated promptly, as the incidence of disease approaches 20% per year in these patients in the absence of prophylaxis. The first-line agent is trimethoprim-sulfamethoxazole (TMP-SMX), one double-strength tablet daily. Dapsone (100 mg/day) is recommended for patients who are TMP-SMX-intolerant and not G6PD-deficient. When the CD4 count falls below 100 cells/mm³, patients with positive T gondii IgG serologies require prophylaxis to prevent reactivation. Daily TMP-SMX is again the drug of choice. Patients receiving dapsone require the addition of pyrimethamine. Although Mycobacterium avium complex (MAC) prophylaxis is recommended at CD4 counts below 50 cells/mm³, initiation is never emergent and active MAC disease should be ruled out before starting prophylaxis if the patient has any suggestive symptoms. The most common regimen is azithromycin 1200 mg/week. More detailed information can be obtained from the USPHS/IDSA guidelines for prevention of opportunistic infections.

Highly Active Antiretroviral Therapy
In the past decade, selection of highly active antiretroviral therapy (HAART) has become increasingly complex. A single regimen is no longer appropriate for all patients, even as initial therapy. Furthermore, textbook chapters become obsolete almost as soon as they are printed, as new classes and new agents become available and recommendations for use change. Appropriate individualized selection of HAART should be left to an HIV specialist.

The ideal time to start HAART therapy remains unclear. Recent guidelines suggest initiating HAART later than previously recommended because of the emerging problems of drug resistance and medication side effects coupled with uncertain benefit. Although the decision to start HAART must be individualized in every case, current guidelines suggest considering initiation of therapy when the CD4 count falls below 350 cells/mm³ or the viral load rises above 55,000 copies/mL (See DHHS Adult/Adolescent Guidelines).

Current therapy should always include a minimum of three agents and often more, selected from among three presently licensed drug classes: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors. Agents in other classes, such as fusion inhibitors, chemokine receptor antagonists, and integrase inhibitors are in development.

Once HAART is initiated, the most critical and modifiable factor affecting success is patient adherence. Only 45% of patients taking 90% to 95% of their prescribed doses of antiretroviral medications will achieve viral suppression (< 400 copies/mL) compared with 78% in those taking more than 95% of their doses.¹⁴ Incomplete viral suppression leads to development of drug resistance. Adherence to the antiviral regimen should be addressed at every visit with every physician in a detailed fashion, and the importance of careful adherence should be stressed. Treatment of pregnant women and children poses special considerations and will not be discussed in detail (See Pediatric and Pregnant Women guidelines).

Side effects of the currently available antiretroviral agents are considerable, and the general practitioner should be aware of them (Table 4). Those which are most common and potentially serious include cytopenias with zidovudine; pancreatitis with didanosine; peripheral neuropathy with didanosine and stavudine; hypersensitivity, including rash, fever, and risk of death with reexposure to abacavir; rash with all NNRTIs; hepatitis with nevirapine; nephrolithiasis with indinivir; and GI toxicity, including diarrhea and nausea, with all protease inhibitors.

More recently appreciated are the metabolic abnormalities that can occur in patients taking HAART. Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia should be carefully monitored and treated (with attention to interactions between the protease inhibitors and many HMG CoA reductase inhibitors). Lipid distribution abnormalities (lipodystrophy) are frequently noted, including wasting of the limbs and face as well as enlargement of the dorsocervical fat pad and central obesity. An increased risk of osteopenia and aseptic joint necrosis has been noted. Mitochondrial dysfunction with potentially fatal lactic acidosis is well described.

In addition, significant drug interactions can occur between antiretroviral agents and commonly prescribed drugs that can lead either to drug toxicities or reduction in levels of the drug or the antiretroviral agent, rendering them ineffective. For a complete listing of adverse effects, toxicities, and medication interactions, refer to the DHHS Adult/Adolescent Guidelines.

The advent of HAART has improved mortality for HIV-infected patients who have access to these medications. In the United States, deaths due to AIDS declined sharply in 1996 and 1997, when protease inhibitors were first introduced. Death rates decreased from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years by 1997 in a cohort of adults with advanced HIV infection.¹⁵ Recent data in a pediatric population mirror these results.¹⁶ Morbidity has declined as well, as measured by the incidence of opportunistic infections.¹⁵ Between 1994 and 1997, the incidence of PCP, MAC disease, and cytomegalovirus retinitis combined decreased by 83% (21.9/100 person-years to 3.7/100 person-years). By 1999, the percent decline in estimated deaths each year due to AIDS had begun to plateau. Current efforts are focused on improving ease of use and decreasing toxicity of HAART in hopes of enhancing the quality of life among those infected with HIV.

The following guidelines are all available at: www.hivatis.org

• DHHS Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, February 4, 2002. Accessed March 9, 2002.
  
  
• Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to reduce Perinatal HIV-1 Transmission in the United States, February 4, 2002. Accessed March 9, 2002.
  
  
• NPHRC/HRSA/NIH Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, December 14, 2001. Accessed March 9, 2002.
  
  
• 2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus, US Public Health Service and Infectious Diseases Society of America. Accessed March 9, 2002.

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10. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996;335:1621-1629.
    
    
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16. Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med. 2001;345:1522-1528.

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