Introduction
Human immunodeficiency virus (HIV) infection in the United States has evolved over the past three decades from an untreatable illness that predictably led to death to a chronic disease that can be medically managed, with life expectancy for many patients similar to that for the general population. Most patients who take combination antiretroviral therapy (ART) experience immune reconstitution and resume normal lives.
Natural History of HIV Infection
Pathogenesis
HIV infection is characterized by an initial, occasionally symptomatic acute phase followed by an asymptomatic period of variable length, culminating in clinically evident immunodeficiency unless treatment is initiated. In HIV infection, persistent immune activation is manifested by increased turnover of T cells, monocytes, and natural killer; high levels of CD4 and CD8 T-cell apoptosis; and polyclonal B-cell activation with hypergammaglobulinemia. Immune activation is strongly predictive of HIV disease progression.
Continuous CD4 T-cell loss and replenishment lead to immunodeficiency because the regenerative capacity of CD4 cells dwindles despite apparent excess of homeostatic cytokines in the peripheral blood and lymphoid tissue. Exhaustion of the T-cell reserve may be due to direct killing by the virus, virus-induced apoptosis, immunologic senescence, and destruction of lymphoid tissue from fibrosis induced by inflammatory cytokines.
Transmission of HIV and progression of disease can be accelerated by bacterial and viral coinfections, which may augment immune activation through upregulation of HIV replication.
When the CD4 lymphocyte count falls below 200 cells/μL of blood, the patient has progressed to the acquired immunodeficiency syndrome (AIDS), characterized by profound deficiency in cell-mediated immunity and resultant increased susceptibility to opportunistic infections (OIs) and certain forms of cancer.
HIV Viral Transmission
The majority of new HIV infections are acquired through sexual intercourse. In resource-limited areas, vaginal sex is the most common means of acquisition. In the United States, male-to-male sexual intercourse is the most common route. Perinatal transmission and exposure to infected blood, such as through intravenous drug use, account for the remaining infections. The risk of transmission correlates with HIV viral load (measured as the number of virus ribonucleic acid [RNA] copies per milliliter [mL] of blood), and risk of sexual transmission increases in the presence of other sexually transmitted infections.
Acute and Early HIV Infection
After the HIV virus enters the body through a mucosal surface or the bloodstream, it infects CD4 T lymphocytes ( Table 18.1 ). There is a period of rapid viral replication leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million viral copies per milliliter of blood. Clinicians must have a high index of suspicion for acute HIV infection, given implications of the high viremia for the patient and public health due to increased risk of transmission.
| Viral Transmission |
| Acute HIV Infection Also known as primary HIV infection, infection occurring within the first several weeks after acquisition. During this phase, HIV RNA and/or p24 antigen are detectable and HIV antibodies are not yet present. Acute retroviral syndrome refers to the clinical manifestations many patients develop during acute HIV infection. |
| Early HIV Infection The 6-month period after acquisition. |
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This high viremia is accompanied by a marked drop in circulating CD4+ T cells. Acute viremia is associated with the activation of CD8+ T cells, which kills HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T-cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T-cell counts partially rebound. A good CD8+ T-cell response does not eliminate the virus but has been linked to slower disease progression and a better prognosis.
By about 6 months after the primary infection, plasma viremia reaches a steady state, known as the viral set point. The set point, which is variable among patients, can be predictive of the rate of clinical progression to AIDS in the absence of ART.
Chronic HIV Infection
During the chronic phase of HIV infection, the consequences of generalized immune activation coupled with the gradual loss of the ability to generate new T cells appear to account for the gradual reduction in CD4+ T cells. Many patients with chronic HIV infection are asymptomatic. Often, it is not until a substantial decline in the CD4 count occurs that patients manifest symptoms. Some patients with HIV infection experience symptoms even before significant CD4 declines, including vaginal candidiasis, recurrent herpes simplex, reactivation of herpes zoster, oral hairy leukoplakia, seborrheic dermatitis, folliculitis, cervical and anal dysplasia, chronic diarrhea, and thrombocytopenia (idiopathic thrombocytopenic purpura).
AIDS
CD4+ T-cell depletion and chronic inflammation drive HIV pathogenesis and progression to AIDS. In patients not on ART, CD4 count progressively declines over time. The largest percentage in CD4 cell decline is seen in early infection, with a more gradual decline once out of the early stage of infection. The symptoms of immune deficiency characteristic of AIDS typically do not appear for years after a person is infected. AIDS is defined as a CD4 cell count below 200 cells/μL or the occurrence of any AIDS-defining condition, as outlined later in this chapter. Certain OIs, namely disseminated Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) disease, are more likely to occur with advanced HIV infection, when the CD4 cell count is below 50 cells/μL. Once the infection has progressed to advanced HIV disease, life expectancy is usually less than 12 to 18 months unless ART is initiated.
Elite Controllers
Elite controllers are a rare group (1%) of HIV-positive individuals who maintain undetectable viral loads and a high CD4 cell count in the absence of ART. They appear to be long-term nonprogressors for clinical HIV disease and do not progress to AIDS-defining illness. This condition is not fully understood and may be associated with certain human leukocyte antigen (HLA) haplotypes. These patients still exhibit immune activation but at a much lower level. Thus they may still be at risk for noninfectious complications of HIV compared with non–HIV-infected patients. It is not known if elite control is an indefinite state. These individuals may eventually require treatment to avoid the development of HIV complications or AIDS.
HIV-2 Infection
HIV-1 is responsible for the vast majority (95%) of HIV infections worldwide. HIV-2 is rarely reported in the United States and is largely confined to persons from West Africa. Compared with HIV-1 infection, the clinical course of HIV-2 infection is generally less aggressive. HIV-2 infection is characterized by a longer asymptomatic stage, lower plasma HIV-2 RNA levels, and lower mortality; however, progression to AIDS does occur. HIV-2 causes a significant number of infections in West Africa and in areas with strong socioeconomic ties to West Africa (e.g., France, Spain, Portugal, and former Portuguese colonies such as Brazil, Angola, Mozambique, and parts of India).
Acute and Early HIV Infection: Clinical Manifestations and Diagnosis
Clinical Manifestations of the Acute Retroviral Syndrome
The acute retroviral syndrome refers to the manifestations many develop during acute infection. These symptoms can range from asymptomatic infection, to a “mononucleosis”-like syndrome, to a severe febrile illness. Symptoms typically manifest within 28 days of infection and most commonly include fever, fatigue, myalgia, rash, headache, pharyngitis, and adenopathy ( Table 18.2 ). Symptoms persist for a median 14 days. Occasionally, acute infection can cause a significant decline in CD4 counts, which may lead to oropharyngeal candidiasis or other OIs.
| Feature | % |
|---|---|
| Fever | 75 |
| Fatigue | 68 |
| Myalgia | 49 |
| Skin rash | 48 |
| Headache | 45 |
| Pharyngitis | 40 |
| Cervical adenopathy | 39 |
| Arthralgia | 30 |
| Night sweats | 28 |
| Diarrhea | 27 |
Laboratory Diagnosis of Acute and Early HIV Infection
HIV can be diagnosed through blood and saliva tests, most of which can detect HIV between 2 and 12 weeks after infection ( Fig. 18.1 ). The fourth-generation p24 antigen–HIV antibody test is the most accurate in use (>99.7% sensitivity and >99.3% specificity) and is recommended as the initial screening test for HIV infection, unless acute infection is suspected. The p24 antigen is a viral core protein that appears in the blood as the viral RNA level rises after HIV infection. In patients suspected of having acute HIV infection, both HIV RNA and HIV antibody testing is recommended. If HIV antibody testing is negative and p24 antigen is positive, individuals should have follow-up testing to document HIV antibody seroconversion.
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HIV RNA (viral load) : detectable approximately 10 days after HIV infection
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Fourth-generation p24 antigen–HIV antibody test : detectable 15 to 20 days after HIV infection Detection of p24 antigen occurs approximately 1 week sooner than the HIV antibody, providing an advantage over third-generation testing. See Fig. 18.2 for interpretation of the fourth-generation antigen–antibody test.
Fig. 18.2
Interpretation of fourth-generation p24 antigen–HIV antibody screening test with confirmatory HIV-1/HIV-2 antibody differentiation assay.
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HIV antibody testing by Western blot : Detectable between 3 and 6 weeks after infection.
HIV Screening
Health care professionals should offer HIV testing to anyone who requests it, and everyone should be tested at least once ( Table 18.3 ). All pregnant women should also be offered testing, usually twice during the pregnancy. Individuals at high risk for HIV infection should be offered testing at least once a year. Risk-based testing alone has not been effective, as providers seldom adequately assess risk. Due to deficiencies in assessing risk and failure to optimize screening, approximately 10% to 25% of persons with undiagnosed HIV are unaware of any risk factors or are uncomfortable disclosing them, and almost half of patients are identified late in the course of disease.
| Organization | Screening Recommendation |
|---|---|
| Centers for Disease Control and Prevention (CDC) | Screen everyone between age 13 and 64 at least once using an opt-out approach. Screen high-risk patients annually. |
| US Preventive Services Task Force (USPSTF) | Screen all adolescents and adults age 15–65, younger adolescents and older adults at higher risk, and pregnant women. |
| American Academy of HIV Medicine | Screen all adults regardless of risk. |
Initial Evaluation of the HIV-Infected Adult
The goals of the initial evaluation of the HIV-infected adult are to (1) confirm diagnosis, (2) assess stage of HIV infection, (3) determine risk for and presence of any concurrent infectious diseases, (4) identify any comorbid conditions that may influence HIV treatment, and (5) select an appropriate antiretroviral regimen. These goals are achieved through a comprehensive history and physical examination and evaluation of laboratory studies and imaging data. Educating the patient about their HIV infection and establishing a therapeutic alliance is of utmost importance at the initial visit.
Confirming HIV Infection
For patients with a prior diagnosis of HIV infection, every effort should be made to review documentation of prior HIV antibody and HIV viral load testing. If this documentation is not available, confirming diagnosis with HIV antibody testing is prudent. Rarely, misdiagnosis or factitious HIV infection has occurred.
For those with a suspected infection, confirm with the appropriate diagnostic test (see Fig. 18.2 ). For patients with suspected acute HIV infection, HIV viral load is the most sensitive and specific means of identifying early infection. Even our best serologic test, the fourth-generation combined antigen–antibody test, may take up to 20 days to turn positive. For those undergoing routine screening or those in whom acute infection is not clinically suspected, the fourth-generation HIV antigen–antibody testing is appropriate.
Comprehensive Medical History
A comprehensive medical history should focus on HIV-specific issues, the presence of other infectious diseases, medical comorbidities that may affect prognosis or treatment, and risk factors for HIV transmission or acquisition of other infections. For those patients with an established HIV diagnosis, a detailed history of prior treatment regimens is essential.
HIV-Specific History
HIV-specific issues to discuss at the initial evaluation include:
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Method and date of suspected acquisition
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Duration of infection, if known
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Behaviors that increase the risk of transmission, such as unprotected sexual intercourse or injection drug use
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Any prior use of pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP)
HIV-specific issues to discuss for patients with a prior HIV diagnosis additionally include prior treatment regimens, prior history of OIs, HIV-related malignancies or other comorbid conditions, and prior CD4 count and viral load results.
Past Medical History
A thorough past medical history should include assessment of prior OIs or AIDS-defining conditions ( Table 18.4 ), common coinfections, and underlying comorbidities that may affect the course and treatment of HIV infection.
| Candidiasis, esophageal or respiratory Invasive cervical cancer Coccidioidomycosis Cryptococcosis Cryptosporidiosis Cytomegalovirus disease Encephalopathy, HIV-related Herpes simplex virus disease Histoplasmosis Isosporiasis Kaposi sarcoma Lymphoma, multiple forms Tuberculosis Nontuberculous mycobacterium infections, pulmonary or extrapulmonary Pneumocystis jirevicii pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis, brain Wasting syndrome of HIV |
Common coinfections include hepatitis B and C and other sexually transmitted infections, including gonorrhea, chlamydia, syphilis, anogenital warts, and herpes simplex virus. A history of tuberculosis or risk for exposure to tuberculosis should be sought, given the greater risk of activation of latent infection among HIV-infected patients. Prior anocervical dysplasia should also be assessed.
All patients should be assessed for cardiometabolic risk factors and disease because their presence may alter HIV treatment. Evalute for smoking, hypertension, diabetes mellitus, dyslipidemia, renal insufficiency, bone disease, peripheral neuropathy, and coronary artery disease. The presence of non–AIDS-defining malignancy, prior cancer screening, and family history of malignancy should be determined. An assessment of a patient’s psychiatric and substance use history is essential to promoting treatment adherence and retention in care.
A current medication and allergy history is necessary to safely prescribe ART. Prior immunization history should be obtained, and immunity to hepatitis A and B should be documented even if previously vaccinated.
Social History
Social history allows the provider to determine the risk of HIV transmission and acquisition of other infectious diseases and to identify barriers to retention in care.
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Employment history and insurance status
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Housing security, safety, and stability
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Thorough travel history to assess potential infectious exposures
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Substance use, past and current
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Tobacco history
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Sexual history, including all exposure sites, use of contraception, and status of partners, if known
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Social support
Family History
A family history of cardiometabolic disease and malignancy should be ascertained.
Review of Systems
A thorough review of systems can identify symptoms concerning for OI or other HIV-related illness. Particular attention should be paid to visual symptoms, respiratory symptoms such as chronic cough or shortness of breath, gastrointestinal symptoms such as dysphagia or odynophagia, skin changes, neurologic changes such as headache, cognitive changes, and weakness or paresthesias.
Comprehensive Physical Examination
A complete examination should be performed at the initial encounter, with particular attention paid to:
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General appearance, weight, lipodystrophy, or wasting
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Skin, including bruising, rashes, or lesions
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Lymph nodes
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Eye, including retinal examination and visual acuity
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Oropharynx, including dentition
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Genitourinary
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Anorectal
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Neurologic, including presence of neuropathy or weakness
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Cognitive status
Initial Laboratory Tests
Laboratory testing should evaluate HIV-specific parameters, organ function, and presence of coinfections ( Table 18.5 ).
