Definition and Epidemiology

Human immunodeficiency virus type 1 (HIV-1) is a member of the family of viruses known as retroviruses. HIV-1 was first isolated in 1985, at which time it was identified as the causative agent underlying the recently identified epidemic of acquired immunodeficiency syndrome (AIDS). HIV-1 is a zoonosis that was transmitted from chimpanzees to humans three or more times early in the 20th century. HIV-2 is a genetically distinct retrovirus that was transmitted from monkeys to humans; it also causes AIDS (although on average more slowly than does HIV-1) but is much less prevalent, both globally and in the United States, than HIV-1.

HIV infection presents a number of challenges for the health care provider. These include when to consider the diagnosis and to test for infection, when to initiate antiretroviral therapy (ART) and with which antiretrovirals (ARVs), and how to monitor disease progression and treatment efficacy. There is a need for close attention to avoid dangerous drug-drug interactions when patients are being treated with ART. The health care provider must also decide how to incorporate risk reduction counseling into clinical care to further reduce HIV transmission. Advice and support around family planning and pregnancy will be needed. When to recommend pre-exposure prophylaxis (PrEP) for those at high risk for acquiring HIV from an infected partner or postexposure prophylaxis after a possible exposure to HIV are other considerations.

The first AIDS case definition was developed by the Centers for Disease Control (CDC) in 1987 as a tool to aid in the study of the epidemiology of the AIDS epidemic. This definition encompassed a mixture of syndromes, primarily opportunistic infections and malignant neoplasms, associated with advanced immune dysfunction.¹ The AIDS case definition has subsequently been expanded several times and now requires that an individual have laboratory documentation of HIV infection and either (1) one of a broad spectrum of opportunistic infections, malignant neoplasms, and nonspecific syndromes or (2) a CD4 cell count of less than 200/mm³.² Because AIDS is a clinical case definition used primarily for epidemiologic monitoring, once an individual is diagnosed with AIDS, that individual will always carry the diagnosis of AIDS, even after immune restoration such that the CD4 cell count is greater than 200/mm³ and all complications of AIDS have resolved.

In addition to the AIDS case definition, several systems were used in the past to classify HIV-infected patients by degree of immune dysfunction, usually based on a combination of laboratory and clinical criteria, but these classification systems were developed before the dynamic nature of HIV infection became clear and before effective treatment became available. They have little usefulness for the clinician caring for HIV-infected patients.

Transmission of HIV can occur sexually, parenterally through either injection drug use or blood product transmission, and vertically from mother to child during pregnancy or through breastfeeding. The risk of sexual transmission varies by the nature of the sexual encounter but is generally in the range of 0.1% to 1% per episode of vaginal or rectal sex when no barrier protection is used. The risk of transmission through oral sex is markedly lower. Factors that increase the risk of transmission include other active sexually transmitted diseases (STDs) and a high HIV viral load. Transmission from blood products was virtually eliminated in the United States in 1985 when it became possible to screen blood donations for HIV. The risk of transmission from an untreated HIV-infected mother to child is 20% to 30% during pregnancy and delivery, with a subsequent risk of transmission through breastfeeding that is cumulative and depends on duration and consistency of breastfeeding.

The CDC estimates that more than 1.2 million people aged 13 or older were living with HIV infection in the United States as of the end of September, 2015 and that an estimated 50,000 people are infected annually.³ Through 2012, the cumulative number of AIDS cases reported to the CDC was 1,155,792; this number also included 9905 children younger than 13 years.³ Since 1997, the number of non-Hispanic African Americans living with AIDS has outnumbered the number of non-Hispanic whites. The three states reporting the highest number of cumulative AIDS cases were New York, California, and Florida. Total deaths through 2010 were 636,048, including 4961 children younger than 13 years.³

AIDS has been a reportable condition since 1987, but HIV infection has never been a nationally reportable disease, and consequently the understanding of U.S. epidemiology has been based primarily on AIDS cases. This has provided a picture of trends in the epidemic that is a number of years out of date and has become even less accurate more recently, with the introduction of therapy that can prevent progression of HIV infection to AIDS. On the basis of results from states in which HIV infection is a reportable condition, it is estimated that men who have sex with men (MSM) now account for 62% of all new HIV infections in the United States, followed by heterosexual transmission (28%). Among women with newly diagnosed HIV infection, however, almost 84% of cases are secondary to heterosexual transmission.³ Important trends include a growing disproportion of cases in minorities, a growing proportion of cases in the southern states, and a resurgence of cases among MSM in at least some areas in the United States.

The extent of the HIV epidemic in the United States, the ongoing stigma associated with the disease, and the social and medical marginalization of some of those at highest risk of acquiring HIV infection have resulted in a relatively unsuccessful campaign to diagnose and bring HIV-infected people into care. Recent estimates suggest that as many as a quarter of all people living with HIV infection in the United States have not been diagnosed and that up to another quarter have been diagnosed but are not receiving care. Thus, there are as many as a half-million people with HIV infection who are at risk of disease progression and eventually life-threatening complications of AIDS and who also are likely to be at higher risk of transmitting HIV.

Because of the failure of the original approach to HIV testing, which relied on targeted testing of those identified as being at higher risk of HIV infection, in 2006 the CDC recommended that testing become universal. Opt-out HIV testing should now be offered at least once to all persons aged 13 to 64 years, regardless of risk, and repeated testing of persons with known risk should be performed annually. Testing should be performed in all health care settings and need not include prevention counseling.⁴

Because of the impact of this disease on public health, the Health Resources and Services Administration of the U.S. Department of Health and Human Services has provided dedicated federal funds through the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act for HIV prevention and care services since 1990. In addition to HIV prevention services, allocated through each state, this act provides funding for both uninsured and low-income persons living with HIV infection to access primary and specialty HIV care, dental services, and case management as well as payment for their life-prolonging HIV medications. However, with the recent adoption of the Affordable Care Act, insurance coverage and payment for services are changing rapidly, thus causing confusion for patients. Lapses in insurance coverage lead to missed appointments and inconsistent adherence to therapy. Therefore it is important that all new HIV clients be provided a case manager to help them navigate insurance and other changing health care reimbursement options that may be available to them and to guarantee coverage without any lapses. Despite the high cost of HIV care, and ART in particular, HIV has had a relatively minor impact on U.S. health care and economy, but this is not the case in many economically disadvantaged countries. The Joint United Nations Programme on HIV/AIDS estimates that more than 35 million people worldwide were living with HIV/AIDS as of the end of 2012; of these, 32.1 million were adults, 17.7 million were women, and 3.3 million were children younger than 15 years.⁵ Approximately 95% of people living with HIV infection now live in the developing world, and most of them still do not have access to any form of effective treatment for HIV infection and thus will likely die of AIDS. During 2012 alone, 2.3 million people became infected, and AIDS caused the deaths of an estimated 1.6 million people, including 210,000 children younger than 15 years.⁵

Pathophysiology

Although some aspects of the HIV life cycle and HIV/AIDS pathophysiology still require further study, the general outline is well established. To infect a cell, HIV must attach to two cell surface proteins: first, CD4 and, second, one of two chemokine receptors, CCR5 or CXCR4, which are often referred to as coreceptors. The virus then fuses with the cell surface, followed by release of viral RNA and proteins into the infected cell. The viral RNA is then reverse transcribed to DNA (hence the name retrovirus), and this DNA is transported into the cell nucleus and incorporated into the cellular genome. Various cells, including monocytes-macrophages and dendritic cells, are susceptible to HIV infection, but the CD4 T lymphocyte is the primary target. A CD4 T lymphocyte that is infected by HIV can remain metabolically inactive with latent HIV infection, or it can be activated with resultant active HIV replication. Through mechanisms that are not entirely understood, with the replication of HIV in activated CD4 T cells and the resultant high-level viremia with the subsequent infection of more CD4 T cells, there is an inexorable decline in the total pool of CD4 T cells in the infected person. As the total number of CD4 T cells declines, as measured by the number of circulating CD4 T cells in peripheral blood (often referred to as the CD4 count or T-cell count), there is a steady decline in the functional capacity of the immune system. After sufficient damage, the infected person starts to develop complications of this immune dysfunction and eventually will develop one or more of the many complications of AIDS and die from the disease. With few exceptions, such as tuberculosis (TB), these AIDS-defining conditions seldom occur until the CD4 T-cell count drops below 200 cells/mm³.

The rate of progression of immune dysfunction, monitored by the decline of the CD4 T-cell count in peripheral blood, varies significantly among individuals. Without ART, the average time from initial HIV infection until the development of a first complication of AIDS is about 8 years, and the average time from this first complication to death is another year. However, some individuals progress to AIDS in a few years (occasionally as short as 1 year), and some rare individuals (known as long-term nonprogressors or elite controllers) maintain a normal CD4 T-cell count indefinitely and never develop AIDS.

Clinical Presentation

The clinical presentation of a person with HIV infection varies tremendously, but the spectrum of presentations is determined by the stage of disease and, most important, by whether the person is experiencing primary HIV infection (PHI), is in the period of clinical latency, or has progressed to AIDS. PHI refers to the time after infection but before the infected person has established a comprehensive immunologic response to infection—that is, the period when HIV can be identified in the person’s blood but before standard serologic test results for HIV have become positive. This period before seroconversion (commonly referred to as the window period) typically lasts several weeks but rarely may be as long as 3 months. During this time, the infected person may experience a seroconversion illness, which is often described as influenza-like but is highly variable and most often consists of fever, myalgia, headache, and a pleomorphic rash.

During the years between PHI and AIDS, a person infected with HIV is typically asymptomatic; however, assorted clinical syndromes may occur during this period. It is important to be aware of these, both for management of a known HIV-infected patient and as indications to consider underlying HIV infection in as yet undiagnosed patients. On occasion, opportunistic infections occur at a CD4 range of more than 200 cells/mm³; but in the United States, the more frequent although still rare severe complications at these higher CD4 counts are malignant neoplasms, the most important of which are lymphomas of various types (excluding the primary central nervous system lymphoma of advanced AIDS) and cervical and anal carcinoma. The most important severe infection that does occur at a higher rate in this CD4 range is TB. Less severe complications in this range include shingles, severe psoriasis, severe (particularly bacteremic) pneumococcal disease, recurrent oral and vaginal candidiasis, oral hairy leukoplakia, and idiopathic thrombocytopenia. The occurrence of any of these conditions in a patient without known HIV infection should result in assessment of risk for HIV infection and frequently in HIV serologic testing.

When a person infected with HIV has progressed to the severe immune dysfunction present in AIDS, he or she becomes at risk for all the potential complications thereof, and development of any one of these mandates testing for HIV infection. The risk for development of an HIV-associated complication increases steadily as the CD4 count drops below 200/mm³. A few of the more common of the earlier complications are Pneumocystis jiroveci pneumonia (PJP), Kaposi sarcoma (KS, a primarily cutaneous malignant neoplasm that manifests as raised violaceous macules), cryptococcal meningitis, and esophageal candidiasis. At lower CD4 counts, especially below 50 cells/mm³, additional complications may develop, including Toxoplasma encephalitis, disseminated Mycobacterium avium-intracellulare complex (MAC) infection, cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy, AIDS dementia, primary central nervous system lymphoma, and AIDS wasting syndrome.

The evaluation of a person newly diagnosed with HIV infection is extensive. If the patient has an acute illness, whether from acute or chronic HIV infection, evaluation and management of that illness take priority; but whether the patient is ill or asymptomatic, the assessment needs to include a comprehensive history and physical examination and extensive laboratory evaluation and other testing. Aspects of the history that require particular attention include the following: