AIDS

In June 1981 scientists published the first report of a mysterious and fatal illness that initially appeared to affect only homosexual men. Subsequent early reports speculated that this illness resulted from homosexual men's sexual activity and, possibly, recreational drug use. In the months that followed, however, this same illness was diagnosed in newborns, children, men, and women, a pattern strongly suggesting a blood-borne infection as the cause of the observed illness. The illness was initially identified by several terms (e.g., "gay bowel syndrome," "lymphadenopathy virus (LAV)," and AIDS-associated retrovirus (ARV), but by 1982 this disease came to be known as acquired immune deficiency syndrome (AIDS) because of the impact of the infectious agent, human immunodeficiency virus (HIV), on an infected person's immune system. Since about 1995 the term HIV disease has been used to describe the condition of HIV-infected persons from the point of early infection through the development of AIDS.

Over the next two decades AIDS became one of the leading causes of death in the United States and in other parts of the world, particularly in persons younger than forty-five years of age. Since the 1990s in the United States AIDS has come to be viewed as an "equal opportunity" disease, because it affects persons of all colors, class, and sexual orientation. Despite the evolution of major treatment advances for HIV infection and AIDS, HIV disease has been the cause of death for about 450,000 persons living in the United States since the onset of the epidemic. In addition, an estimated 800,000 to 900,000 Americans are infected with the virus that causes AIDS—and perhaps as many as 300,000 are unaware of their infection. Better treatments for HIV infection have resulted in a reduction in the number of deaths from AIDS and an increase in the number of persons living with HIV infection.

The cause of AIDS was identified in 1983 by the French researcher Luc Montagnier as a type of virus known as a "retrovirus." This newly identified retrovirus was eventually called "human immunodeficiency virus," or HIV. Scientists have established HIV as the cause of AIDS, even though a small group of individuals have questioned the link between HIV and AIDS. An HIV-infected person who meets specific diagnostic criteria (i.e., has one or more of the twenty-five AIDS-defining conditions indicative of severe immunosuppression and/or a seriously compromised immune system) is said to have AIDS, the end stage of a continuous pathogenic process. Multiple factors influence the health and functioning of HIV-infected persons. For example, some persons who meet the diagnostic criteria for AIDS may feel well and function normally, while other HIV-infected persons who do not meet the diagnostic criteria for AIDS may not feel well and have reduced functioning in one or more areas of their lives.

While drugs are now available to treat HIV infection or specific HIV-related conditions, these treatments are expensive and unobtainable to most of the world's infected individuals, the vast majority of whom live in poor, developing nations. Thus the most important and effective treatment for HIV disease is prevention of infection. Preventive measures are challenging because sexual and drug use behaviors are difficult to change; certain cultural beliefs that influence the potential acquisition of infection are not easily modified; many persons at highest risk lack access to risk-reduction education; and many persons (especially the young) deny their vulnerability to infection and engage in behaviors that place them at risk of infection.

An individual may be infected with HIV for ten years or more without symptoms of infection. During this period, however, the immune system of the untreated person deteriorates, increasing his or her risk of acquiring "opportunistic" infections and developing certain malignancies. While HIV disease is still considered a fatal condition, the development in the 1990s of antiretroviral drugs and other drugs to treat opportunistic infections lead many infected individuals to hope that they can manage their disease for an extended period of time. Unfortunately, the view that HIV disease is a "chronic" and "manageable" condition (as opposed to the reality that it is a fatal condition) may lead persons to engage in behaviors that place them at risk of infection. In the United States, for example, epidemiologists have noted an upswing in the number of HIV infections in young homosexual men who, these experts believe, engage in risky behaviors because HIV disease has become less threatening to them. These individuals are one generation removed from the homosexual men of the 1980s who saw dozens of their friends, coworkers, and neighbors die from AIDS and thus may not have experienced the pain and grief of the epidemic's first wave.

Origin of HIV

The origin of the human immunodeficiency virus has interested scientists since the onset of the epidemic because tracing its history may provide clues about its effects on other animal hosts and on disease treatment and control. While HIV infection was first identified in homosexual men in the United States, scientists have learned from studies of stored blood samples that the infection was present in human hosts years—and perhaps decades—before 1981. However, because the number of infected individuals was small and the virus was undetectable prior to 1981, a pattern of disease went unrecognized. HIV disease may have been widespread, but unrecognized, in Africa before 1981.

While a number of theories, including controversial conspiracy theories, have been proposed to explain the origin of HIV and AIDS, strong scientific evidence supports the view that HIV represents a cross-species (zoonosis) infection evolving from a simian (chimpanzee) virus in Southwest Africa between 1915 and 1941. How this cross-species shift occurred is unclear and a topic of considerable debate. Such an infectious agent, while harmless in its natural host, can be highly lethal to its new host.

Epidemiology of HIV Disease

Because HIV has spread to every country of the world, it is considered a pandemic. By the end of 2001 an estimated 65 million persons worldwide had been infected with HIV and of these, 25 million had died. An estimated 14,000 persons worldwide are infected every day. Most (95%) of the world's new AIDS cases are in underdeveloped countries. About 70 percent of HIV-infected persons live in sub-Saharan Africa. Globally 1 in 100 people are infected with HIV. The effects of HIV disease on the development of the world have been devastating. Millions of children in developing nations are infected and orphaned. The economies of some developing nations are in danger of collapse; and some nations risk political instability because of the epidemic.

Over the past decade an estimated 40,000 persons living in the United States have become infected with HIV every year, a figure that has remained relatively stable. Between 1981 and 2000 more than 774,000 cases of AIDS were reported to the Centers for Disease Control and Prevention (CDC). Of these cases, more than 82 percent were among males thirteen years and older, while more than 16 percent were among females thirteen years and older. Less than 2 percent of AIDS cases were among children younger than thirteen years of age. More than 430,000 persons living in the United States had died from AIDS by the end of 1999. The annual number of deaths among persons with AIDS has been decreasing because of early diagnosis and improved treatments for opportunistic infections and HIV infection.

The epidemiologic patterns of HIV disease have changed significantly since the onset of the epidemic. In 1985, for example, 65 percent of new AIDS cases were detected among men who have sex with other men (MSM). Since 1998 only about 42 percent of new AIDS cases have been detected among MSM, although the rate of new infections in this group remains high. Increasing numbers of new AIDS cases are attributed to heterosexual contact (but still only about 11 percent of the cumulative AIDS cases) and among injection drug users (about 25 percent of cumulative AIDS cases). In 2002 women, who are primarily infected through heterosexual contact or injection drug use, account for about 30 percent of all new HIV infections, a dramatic shift in the United States since 1981. In developing parts of the world men and women are infected in equal numbers.

In the United States new HIV infections and AIDS disproportionately affect minority populations and the poor. Over half (54%) of new HIV infections occur among African Americans, who represent less than 15 percent of the population. Hispanics are disproportionately affected as well. African-American women account for 64 percent (Hispanic women, 18%) of new HIV infections among women. African-American men account for about half of new HIV infections among men, with about equal numbers (18%) of new infections in white and Hispanic men. HIV infections in infants have been dramatically reduced because of the use of antiretroviral drugs by HIV-infected women who are pregnant.

HIV Disease: The Basics

There are two major types of human immunodeficiency virus: HIV-1 and HIV-2. HIV-1 is associated with most HIV infections worldwide except in West Africa, where HIV-2 is prevalent. Both types of viruses may be detected through available testing procedures. HIV is a retrovirus and member of a family of viruses known as lentiviruses, or "slow" viruses. These viruses typically have a long interval between initial infection and the onset of serious symptoms. Lentiviruses frequently infect cells of the immune system. Like all viruses, HIV can replicate only inside cells, taking over the cell's machinery to reproduce. HIV, once inside a cell, uses an enzyme called reverse transcriptase to convert ribonucleic acid (RNA) into deoxyribonucleic acid (DNA), which is incorporated into the host cell's genes. The steps in HIV replication include: (1) attachment and entry; (2) reverse transcription and DNA synthesis; (3) transport to nucleus; (4) integration; (5) viral transcription; (6) viral protein synthesis; (7) assembly and budding of virus; (8) release of virus; and (9) maturation. In addition to rapid replication, HIV reverse transcriptase enzyme makes many mistakes while making DNA copies from HIV RNA, resulting in multiple variants of HIV in an individual. These variants may escape destruction by antibodies or killer T cells during replication.

The immune system is complex, with many types of defenses against infections. Some parts of this system have key coordinating roles in mobilizing these defenses. One such key is the CD4 + T-lymphocyte (also known as CD4 + T cell and T-helper cell), a type of lymphocyte that produces chemical "messengers." These messengers strengthen the body's immune response to infectious organisms. The cell most markedly influenced by HIV infection is the CD4 + T-lymphocyte. Over time HIV destroys these CD4 + T cells, thus impairing the immune response of people with HIV disease and making them more susceptible to secondary infections and some types of malignant tumors.

If HIV infection progresses untreated, the HIV-infected person's number of CD4 + T-lymphocytes declines. Therefore, early in the course of HIV disease the risk for developing opportunistic infections is low because the CD4 + T-lymphocytes may be nearly normal or at least adequate to provide protection against pathogenic organisms; however, in untreated individuals the risk of infection increases as the number of CD4 + cells falls. The rate of decline of CD4 + T lymphocyte numbers is an important predictor of HIV-disease progression. People with high levels of HIV in their bloodstream are more likely to develop new AIDS-related symptoms or die than individuals with lower levels of virus. Thus early detection and treatment of HIV infection and routine use of blood tests to measure viral load are critical in treating HIV infection. HIV may also directly infect other body cells (e.g., those of the brain and gastrointestinal tract), resulting in a range of clinical conditions. When cells at these sites are infected with HIV, such problems as dementia and diarrhea may result; thus even if HIV-infected persons do not develop an opportunistic infection or malignancy, they may experience a spectrum of other clinical problems that require medical treatment or interfere with their quality of life.

How Is HIV Spread?

The major known ways by which HIV infection is spread are: (1) intimate sexual contact with an HIV-infected person; (2) exposure to contaminated blood or blood products either by direct inoculation, sharing of drug apparatus, transfusion, or other method; and (3) passage of the virus from an infected mother to her fetus or newborn in utero, during labor and delivery, or in the early newborn (including through breast-feeding). Some health care workers have become occupationally infected with HIV, but these numbers are small in light of the millions of contacts between health care workers and persons with HIV infection. Most occupationally acquired HIV infections in such workers have occurred when established "universal precautions" have not been followed.

HIV-infected blood, semen, vaginal fluid, breast milk, and other bodily fluids containing blood have been proven to have the potential to transmit HIV. While HIV has been isolated from other cells and tissues, the importance of these bodily fluids in transmission is not entirely clear. Health care workers may come into contact with other bodily fluids that can potentially transmit HIV. While HIV has been transmitted between members in a household setting, such transmission is extremely rare. There are no reports of HIV being transmitted by insects; by nonsexual bodily contact (e.g., handshaking); through closed mouth or social kissing; or by contact with saliva, tears, or sweat. One cannot be HIV-infected by donating blood. Transfusion of blood products can pose a risk of infection, but the risk is low in the United States, where all such products are carefully tested.

Several factors (called "cofactors") may play a role in the acquisition of HIV infection, influence its transmission, affect development of clinical signs and symptoms, and influence disease progression. Cofactors that have been mentioned in scientific literature include anal receptive sex resulting in repeated exposure to absorbed semen; coexistence of other infections (e.g., syphilis, hepatitis B); injection and recreational drug use; use of immunosupressant drugs (e.g., cocaine, alcohol, or amyl/butyl nitrites); douching or enemas before sexual intercourse; malnutrition; stress; age at time of seroconversion; genetic susceptibility; multiple sexual partners; and presence of genital ulcers.

Preventing HIV Infection

HIV infection is almost 100 percent preventable. HIV infection may be prevented by adhering to the following measures:

• • engaging in one-partner sex where both participants are HIV-negative and are maintaining a sexual relationship that only involves those two participants;
• • using latex or polyurethane condoms properly every time during sexual intercourse, including oral sex;
• • not sharing needles and syringes used to inject drugs or for tattooing or body piercing;
• • not sharing razors or toothbrushes;
• • being tested for HIV if one is pregnant or considering pregnancy;
• • prohibiting oneself from breast-feeding if HIV-positive; and
• • calling the CDC National AIDS Hotline at 1-800-342-AIDS (2437) for more information about AIDS prevention and treatment (or by contacting www.cdc.gov/hiv to access the CDC Division of HIV/AIDS for information).

What Happens after Infection with HIV?

Following infection with HIV the virus infects a large number of CD4 + cells, replicating and spreading widely, and producing an increase in viral burden in blood. During this acute stage of infection, which usually occurs within the first few weeks after contact with the virus, viral particles spread throughout the body, seeding various organs, particularly the lymphoid organs (lymph nodes, spleen, tonsils, and adenoids). In addition, the number of CD4 + T cells in the bloodstream decreases by 20 to 40 percent. Infected persons may also lose HIV-specific CD4 + T cell responses that normally slow the replication of viruses in this early stage. Within a month of exposure to HIV the infected individual's immune system fights back with killer T cells (CD8 + T cells) and B-cell antibodies that reduce HIV levels, allowing for a rebound of CD4 + T cells to 80 to 90 percent of their original level. The HIV-infected person may then remain free of HIV-related symptoms for years while HIV continues to replicate in the lymphoid organs seeded during the acute phase of infection. Also at this point many infected persons experience an illness (called "primary" or "acute" infection) that mimics mononucleosis or flu and usually lasts two to three weeks.

In untreated HIV-infected persons, the length of time for progression to disease varies widely. Most (80 to 90 percent) HIV-infected persons develop AIDS within ten years of initial infection; another 5 to 10 percent of infected persons progress to AIDS within two to three years of HIV infection; about 5 percent are generally asymptomatic for seven to ten years following infection and have no decline in CD4 + T lymphocyte counts. Efforts have been made to understand those factors that affect disease progression, including viral characteristics and genetic factors. Scientists are also keenly interested in those individuals who have repeated exposures to HIV (and may have been acutely infected at some point) but show no clinical evidence of chronic HIV infection.

Testing and Counseling

Testing for HIV infection has complex social, ethical, legal, and health implications. HIV testing is done for several reasons: to identify HIV-infected persons who may benefit from early medical intervention; to identify HIV-negative persons who may benefit from risk reduction counseling; to provide for epidemiological monitoring; to engage in public health planning. Individuals who seek HIV testing expect that test results will remain confidential, although this cannot be entirely guaranteed. Anonymous testing is widely available and provides an additional measure of confidentiality.

HIV testing has been recommended for those who consider themselves at risk of HIV disease, including:

• • women of childbearing age at risk of infection;
• • persons attending clinics for sexually transmitted disease and drug abuse;
• • spouses and sex- or needle-sharing partners of injection drug users;
• • women seeking family planning services;
• • persons with tuberculosis;
• • individuals who received blood products between 1977 and mid-1995; and
• • others, such as individuals with symptoms of HIV-related conditions; sexually active adolescents; victims of sexual assault; and inmates in correctional facilities.

Detection of HIV antibodies is the most common approach to determine the presence of HIV infection, although other testing approaches can detect the virus itself. Testing for HIV infection is usually accomplished through standard or rapid detection (results are obtained in five to thirty minutes) of anti-HIV antibodies in blood and saliva. The most common types of antibody test for HIV serodiagnosis include the enzyme-linked immunosorbent assay (ELISA), the Western blot, immunofluorescence, radioimmuno-precipitation, and hemagglutination. These tests do not directly measure the presence of the virus but rather the antibodies formed to the various viral proteins. One home testing kit—the Home Access HIV-1 Test System—is approved by the U.S. Food and Drug Administration. Oral and urine-based tests are available for rapid screening in medical offices but are typically followed up by one or more tests for confirmation. Most tests used to detect HIV infection are highly reliable in determining the presence of HIV infection, but false-positive and false-negative results have been documented by Niel Constantine and other health care professionals.

Testing for HIV infection should always include pre- and posttest counseling. Guidelines for such testing have been published by the CDC. Pretest counseling should include information about the test and test results, HIV infection, and AIDS; performance of a risk assessment and provision of information about risk and risk reduction behaviors associated with the transmission of HIV; discussion about the consequences (i.e., medical care, pregnancy, employment, insurance) of a positive or negative result for the person being tested and for others (family, sexual partner(s), friends); and discussion about the need for appropriate follow-up in the event of positive test results. Post–test counseling is dependent upon test results, but generally includes provision of test results, emotional support, education, and, when appropriate, referral for medical or other forms of assistance.

Clinical Manifestations of HIV Disease

The clinical manifestations of HIV vary greatly among individuals and depend upon individual factors and the effectiveness of medical intervention, among other factors. Primary infection may also offer the first opportunity to initiate antiretroviral therapy, although all experts do not agree that such therapy should be initiated at this stage of the infection. The symptom-free period of time following primary infection has been extended in many infected persons by the introduction of highly active antiretroviral therapy (HAART). Many HIV-infected persons, especially those who do not

receive antiretroviral therapy, those who respond poorly to such therapy, and those who experience adverse reactions to these drugs, will develop one or more opportunistic conditions, malignancies, or other conditions over the course of their disease.

Opportunistic Infections

Prior to the HIV epidemic, many opportunistic infections (OIs) seen in HIV-infected persons were not commonly encountered in the health care community. Many of the organisms responsible for these OIs are everywhere (ubiquitous) in the environment and cause little or no disease in persons with competent immune systems. However, in those who are immunocompromised, these organisms can cause serious and life-threatening disease. Since the introduction of HAART the incidence of HIV-related opportunistic infections and malignancies has been declining. The epidemiological patterns of at least some of these opportunistic diseases vary by region and country. Ideally, treatment of OIs is aimed at prevention of infections, treatment of active infections, and prevention or recurrences. Over the course of the HIV epidemic several new drugs and treatment approaches aimed at OIs have been introduced or refined. Guidelines have also been developed concerning the prevention of exposure to opportunistic pathogens.

Opportunistic infections affecting HIV-infected persons fall into four major categories:

1. Parasitic/Protozoa infections—cryptosporidiosis, toxoplasmosis, isosporiasis, and microsporidiosis.
2. Fungal infections—pneumocystosis, cryptococcus, candidiasis (thrush), histoplasmosis, and coccidioidomycosis.
3. Bacterial infections—mycobacterium avium complex (MAC), mycobacterium tuberculosis (TB), and salmanellosis.
4. Viral infections—cytomegalovirus, herpes simplex types 1 and 2, and varicella-zoster virus (shingles), cytomegalovirus, and hepatitis.

Parasitic infections can cause significant illness and death among HIV-infected persons. Fungal diseases may vary widely among persons with HIV disease because many are commonly found in certain parts of the world and less common in others. Bacterial infections are also seen as important causes of illness and death in HIV-infected persons. Viral infections are common in this population and are often difficult to treat because of the limited number of antiviral drugs that are available. Persons with HIV disease often suffer from recurrences of viral infections. Those whose immune systems are severely compromised may have multiple infections simultaneously.

Two categories of malignancies that are often seen in persons with HIV disease are Kaposi's sarcoma (KS) and HIV-associated lymphomas. Prior to the HIV epidemic KS was rarely seen in the United States. Since the mid-1990s, researchers have also suggested an association between cervical and anal cancers. When cancers develop in a person with HIV disease these conditions tend to be aggressive and resistant to treatment.

In addition to the opportunistic infections and malignancies, persons with HIV disease may experience Wasting syndrome and changes in mental functioning. Wasting syndrome is a weight loss of at least 10 percent in the presence of diarrhea or chronic weakness and documented fever for at least thirty days that is not attributable to a concurrent condition other than HIV infection. Multiple factors are known to cause this weight loss and muscle wasting, including loss of appetite, decreased oral intake, and nausea and vomiting. Wasting is associated with rapid decline in overall health, increased risk of hospitalization, development of opportunistic infection, decreased quality of life, and decreased survival. Interventions include management of infections, oral nutritional supplements, use of appetite stimulants, management of diarrhea and fluid loss, and exercise.

AIDS dementia complex (ADC) is a complication of late HIV infection and the most common cause of neurological dysfunction in adults with HIV disease. Its cause is believed to be direct infection of the central nervous system by HIV. This condition can impair the intellect and alter motor performance and behavior. Early symptoms include difficulty in concentration, slowness in thinking and response, memory impairment, social withdrawal, apathy, personality changes, gait changes, difficulty with motor movements, and poor balance and coordination. As ADC advances, the affected person's cognitive functioning and motor skills worsen. Affected persons may enter a vegetative state requiring total care and environmental control. Treatment focuses on supportive care measures and aggressive use of HAART.

Finally, persons with HIV disease frequently experience mental disorders, especially anxiety and depression. These are typically treated by standard drug therapy and psychotherapy. Persons with HIV disease are also at greater risk of social isolation, which can have a negative impact on their mental and physical health.

Management of HIV Disease

Better understanding of HIV pathogenesis, better ways to measure HIV in the blood, and improved drug treatments have greatly improved the outlook for HIV-infected persons. Medical management focuses on the diagnosis, prevention, and treatment of HIV infection and related opportunistic infections and malignancies. HIV-infected persons who seek care from such providers should expect to receive compassionate and expert care in such settings. Management of HIV disease includes:

• • early detection of HIV infection;
• • early and regular expert medical evaluation of clinical status;
• • education to prevent further spread of HIV infection and to maintain a healthy lifestyle;
• • administration of antiretroviral drugs;
• •provision of drugs to prevent the emergence of specific opportunistic infections;
• •provision of emotional/social support;
• • medical management of HIV-related symptoms;
• • early diagnosis and appropriate management of OIs and malignancies; and
• •referral to medical specialists when indicated.

The mainstay of medical treatment for HIV-infected persons is the use of antiretroviral drugs. Goals of antiretroviral therapy are to prolong life and improve quality of life; to suppress virus below limit of detection for as long as possible; to optimize and extend usefulness of available therapies; and to minimize drug toxicity and manage side effects.

Two major classes of antiretroviral drugs are available for use in the treatment of HIV infection—reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). These drugs act by inhibiting viral replication. RTIs interfere with reverse transcriptase, an enzyme essential in transcribing RNA into DNA in the HIV replication cycle. Protease inhibitor drugs work by inhibiting the HIV protease enzyme, thus preventing cleavage and release of mature, infectious viral particles. Dozens of other drugs that may become available in the next few years to treat HIV infection are under development and testing. Because of the high costs of these drugs, individuals needing assistance may gain access to HIV-related medications through the AIDS Drug Assistance Program (ADAP) and national pharmaceutical industry patient assistance/expanded access programs.

Panels of HIV disease experts have released guidelines for the use of antiretroviral agents in infected persons. The guidelines, which are revised periodically to reflect rapidly evolving knowledge relative to treatment, are widely available on the Internet. These guidelines have greatly assisted practitioners to provide a higher standard of care for persons living with HIV disease.

Viral load tests and CD4 + T-cell counts are used to guide antiretroviral drug treatment, which is usually initiated when the CD4 + T-cell count falls below 500 and/or there is evidence of symptomatic disease (e.g., AIDS, thrush, unexplained fever). Some clinicians recommend antiretroviral drug treatment to asymptomatic HIV-infected persons.

Because HIV replicates and mutates rapidly, drug-resistance is a challenge, forcing clinicians to alter drug regimens when these instances occur. Inadequate treatment, poor adherence, and interruptions in treatment increase drug resistance. This resistance can be delayed by the use of combination regimens to achieve CD4 + T-cell counts below the level of detection. Careful adherence to prescribed HAART regimens is crucial in treatment and many interventions have been tried to improve patient adherence. Because some HIV-infected persons are taking multiple doses of multiple drugs daily, adherence challenges patients and clinicians alike. Once antiretroviral therapy has been initiated patients remain on this therapy continuously, although intermittent drug treatment is being studied. Because persons living with HIV disease may take numerous drugs simultaneously, the potential for drug interactions and adverse reactions is high. These persons typically have a higher incidence of adverse reactions to commonly used drugs than do non-HIV-infected patients.

In the United States HIV/AIDS is an epidemic primarily affecting men who have sex with men and ethnic/racial minorities. Homophobia, poverty, homelessness, racism, lack of education, and lack of access to health care greatly influence testing, treatment, and prevention strategies. While an effective vaccine is crucial to the prevention of HIV, efforts to develop such a vaccine have been unsuccessful to date; therefore, current and future prevention efforts, including behavior modification interventions, must be aimed at ethnic minorities, men who have sex with men, and other high-risk populations. Finally, a safe, effective antiviral product that women can use during sexual intercourse would greatly reduce their risk of infection.

See also: Causes of Death ; Pain and Pain Management ; Suicide Influences and Factors: Physical Illness ; Symptoms and Symptom Management

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JERRY D. DURHAM