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.

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).

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.

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.

  

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  HIV antibody testing by Western blot : Detectable between 3 and 6 weeks after infection.

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.