AIDS is a transmissible disease of the immune system caused by the human immunodeficiency virus (HIV). HIV is a lentivirus (literally meaning "slow virus"; a member of the retrovirus family) that slowly attacks and destroys the immune system, the body's defense against infection, leaving an individual vulnerable to a variety of other infections and certain malignancies that eventually cause death. AIDS is the final stage of HIV infection, during which time fatal infections and cancers frequently arise.THE EMERGENCE OF HIV/AIDS
Details of the origin of HIV remain unclear; however, a lentivirus that is genetically similar to HIV has been found in chimpanzees in western equatorial Africa. This virus, known as simian immunodeficiency virus (SIV), does not readily cause disease in chimpanzees. However, AIDS is a zoonosis, an infection that is shared by humans and lower vertebrate animals. The practice of hunting, butchering, and eating the meat of chimpanzees may have allowed transmission of the virus to humans, probably in the first half of the 20th century.
Genetic studies of two different types of HIV—HIV-1 and HIV-2—demonstrate that the viruses diverged from one another in the 1930s. Researchers estimate that the spread of HIV began in central and western Africa in the late 1950s, with HIV-1 being the predominant infectious form. Later, in the mid-1960s, a subtype of HIV-1 spread from Africa to Haiti. In Haiti this subtype acquired unique characteristics, presumably through the process of genetic recombination. Sometime between 1969 and 1972, the virus migrated from Haiti to the United States. The virus spread within the United States for about a decade before it was discovered in the early 1980s. The worldwide spread of HIV-1 was likely facilitated by several factors, including increasing urbanization and long-distance travel in Africa, international travel, changing sexual mores, and intravenous drug use.
In 1981 investigators in New York and California reported the first official case of AIDS. Initially, most cases of AIDS in the United States were diagnosed in homosexual men, who contracted the virus primarily through sexual contact, and in intravenous drug users, who became infected mainly by sharing contaminated hypodermic needles. In 1983 French and American researchers isolated the causative agent, HIV, and by 1985 serological tests to detect the virus had been developed. According to the 2007 United Nations report on AIDS, an estimated 33.2 million people were living with HIV, approximately 2.5 million people were newly infected with HIV, and about 2.1 million people died of AIDS. Relative to previous years, the statistics for 2007 reflect a decrease in the annual number of new infections and deaths from AIDS and an increase in the overall number of people living with AIDS. Some 25 million people have died of the disease since 1981.
People living in sub-Saharan Africa account for about 70 percent of all infections, and in some countries of the region the prevalence of HIV infection of inhabitants exceeded 10 percent of the population. Rates of infection are lower in other parts of the world, but different subtypes of the virus have spread to Europe, India, South and Southeast Asia, Latin America, and the Caribbean. Rates of infection have leveled off somewhat in the United States and Europe. In the United States nearly one million people are living with HIV/AIDS, and half of all new infections are among African Americans. In Asia the sharpest increases in HIV infections are found in China, Indonesia, and Vietnam. Access to retroviral treatment for AIDS remains limited in some areas of the world, although more people are receiving treatment today than in the past.
GROUPS AND SUBTYPES OF HIV
Genetic studies have led to a general classification system for HIV that is primarily based on the degree of similarity in viral gene sequence. HIV-1 is divided into three groups, known as group M (main group), group O (outlier group), and group N (new group). Worldwide, HIV-1 group M causes the majority of HIV infections, and it is further subdivided into subtypes A through K, which differ in expression of viral genes, virulence, and mechanisms of transmission. In addition, some subtypes combine with one another to create recombinant subtypes. HIV-1 group M subtype B is the virus that spread from Africa to Haiti and eventually to the United States. Pandemic forms of subtype B are found in North and South America, Europe, Japan, and Australia. Subtypes A, C, and D are found in sub-Saharan Africa, although subtypes A and C are also found in Asia and some other parts of the world. Most other subtypes of group M are generally located in specific regions of Africa, South America, or Central America.
HIV-2 is divided into groups A through E, with subtypes A and B being the most relevant to human infection. HIV-2, which is found primarily in western Africa, can cause AIDS, but it does so more slowly than HIV-1. There is some evidence that HIV-2 may have arisen from a form of SIV that infects African green monkeys.
PREVALENCE OF AIDS
AIDS is one of the deadliest epidemics in human history. It was first identified in 1981 among homosexual men and intravenous drug users in New York and California. Shortly after its detection in the United States, evidence of AIDS epidemics grew among heterosexual men, women, and children in sub-Saharan Africa. AIDS quickly developed into a worldwide epidemic, affecting virtually every nation. The United Nations Program on HIV/AIDS (UNAIDS) estimates that the worldwide number of new cases of HIV infection peaked in the late 1990s with more than 3 million people newly infected each year. However, some regions of the world, especially Vietnam, Indonesia, and other countries in southeast Asia, continued to see an increase in the early 2000s. In addition, the number of people living with HIV or AIDS has continued to rise as the result of new drug treatments that lengthen life.While cases of AIDS have been reported in every nation of the world, the disease affects some countries more than others. About 90 percent of all HIV-infected people live in the developing world. AIDS has struck sub-Saharan Africa particularly hard. Two-thirds of all people living with HIV infection reside in African countries south of the Sahara, where AIDS is the leading cause of death.
In countries hardest hit, AIDS has sapped the population of young men and women who form the foundation of the labor force. Most die while in the peak of their reproductive years. Moreover, the epidemic has overwhelmed health-care systems, increased the number of orphans, and caused life expectancy rates to plummet. These problems have reached crisis proportions in parts of the world already burdened by war, political upheaval, or unrelenting poverty.
CAUSE OF AIDS
AIDS is the final stage of a chronic infection with the human immunodeficiency virus. There are two types of this virus: HIV-1, which is the primary cause of AIDS worldwide, and HIV-2, found mostly in West Africa. Inside the body HIV enters cells of the immune system, especially white blood cells known as T cells. These cells orchestrate a wide variety of disease-fighting mechanisms. Particularly vulnerable to HIV attack are specialized "helper" T cells known as CD4 cells. When HIV infects a CD4 cell, it commandeers the genetic tools within the cell to manufacture new HIV virus. The newly formed HIV virus then leaves the cell, destroying the CD4 cell in the process. No existing medical treatment can completely eradicate HIV from the body once it has infected human cells.
The loss of CD4 cells endangers health because these cells help other types of immune cells respond to invading organisms. The average healthy person has over 1,000 CD4 cells per microliter of blood. In a person infected with HIV, the virus steadily destroys CD4 cells over a period of years, diminishing the cells’ protective ability and weakening the immune system. When the density of CD4 cells drops to 200 cells per microliter of blood, the infected person becomes vulnerable to AIDS-related opportunistic infections and rare cancers, which take advantage of the weakened immune defenses to cause disease.
LIFE CYCLE OF HIV VIRUS
The main cellular target of HIV is a special class of white blood cells critical to the immune system known as helper T lymphocytes, or helper T cells. Helper T cells are also called CD4+ T cells because they have on their surfaces a protein called CD4. Helper T cells play a central role in normal immune responses by producing factors that activate virtually all the other immune system cells. These include B lymphocytes, which produce antibodies needed to fight infection; cytotoxic T lymphocytes, which kill cells infected with a virus; and macrophages and other effector cells, which attack invading pathogens. AIDS results from the loss of most of the helper T cells in the body.
HIV is a retrovirus, one of a unique family of viruses that consist of genetic material in the form of RNA (instead of DNA) surrounded by a lipoprotein envelope. HIV cannot replicate on its own and instead relies on the mechanisms of the host cell to produce new viral particles. HIV infects helper T cells by means of a protein embedded in its envelope called gp120. The gp120 protein binds to a molecule called CD4 on the surface of the helper T cell, an event that initiates a complex set of reactions that allow the HIV genetic information into the cell. Entry of HIV into the host cell also requires the participation of a set of cell surface proteins that normally serve as receptors for chemokines (hormone-like mediators that attract immune system cells to particular sites in the body). It appears that the binding of gp120 to CD4 exposes a region of gp120 that interacts with the chemokine receptors. This interaction triggers a conformational change that exposes a region of the viral envelope protein gp41, which inserts itself into the membrane of the host cell so that it bridges the viral envelope and the cell membrane. An additional conformational change in gp41 pulls these two membranes together, allowing fusion to occur. After fusion the viral genetic information can enter the host cell.
Once the virus has infected a T cell, HIV copies its RNA into a double-stranded DNA copy by means of the viral enzyme reverse transcriptase; this process is called reverse transcription because it violates the usual way in which genetic information is transcribed. Because reverse transcriptase lacks the "proofreading" function that most DNA synthesizing enzymes have, many mutations arise as the virus replicates, further hindering the ability of the immune system to combat the virus. These mutations allow the virus to evolve very rapidly, approximately one million times faster than the human genome evolves. This rapid evolution allows the virus to escape from antiviral immune responses and antiretroviral drugs. The next step in the virus life cycle is the integration of the viral genome into the host cell DNA. Integration occurs at essentially any accessible site in the host genome and results in the permanent acquisition of viral genes by the host cell. Under appropriate conditions these genes are transcribed into viral RNA molecules. Some viral RNA molecules are incorporated into new virus particles, while others are used as messenger RNA for the production of new viral proteins. Viral proteins assemble at the plasma membrane together with the genomic viral RNA to form a virus particle that buds from the surface of the infected cell, taking with it some of the host cell membrane that serves as the viral envelope. Embedded in this envelope are the gp120/gp41 complexes that allow attachment of the helper T cells in the next round of infection. Most infected cells die quickly (in about one day). The number of helper T cells that are lost through direct infection or other mechanisms exceeds the number of new cells produced by the immune system, eventually resulting in a decline in the number of helper T cells. Physicians follow the course of the disease by determining the number of helper T cells (CD4+ cells) in the blood. This measurement, called the CD4 count, provides a good indication of the status of the immune system. Physicians also measure the amount of virus in the bloodstream—i.e., the viral load—which provides an indication of how fast the virus is replicating and destroying helper T cells.
Because of the high rate at which the genetic material of HIV mutates, the virus in each infected individual is slightly different. Genetic variants of HIV have been categorized into several major subtypes, or clades, which have different geographical distributions. Variation occurs throughout the genome but is especially pronounced in the gene encoding the gp120 protein. By constantly changing the structure of its predominant surface protein, the virus can avoid recognition by antibodies produced by the immune system.
HOW HIV INFECTION SPREADS
Scientists have identified three ways that HIV infections spread: sexual intercourse with an infected person, contact with contaminated blood, and transmission from an infected mother to her child before or during birth or through breast-feeding.
1. Sex with an Infected Person: HIV transmission occurs most commonly during intimate sexual contact with an infected person, including genital, anal, and oral sex. The virus is present in the infected person’s semen or vaginal fluids. During sexual intercourse, the virus gains access to the bloodstream of the uninfected person by passing through openings in the mucous membrane—the protective tissue layer that lines the mouth, vagina, and rectum—and through breaks in the skin of the penis. In the United States and Canada, HIV is most commonly transmitted during sex between men, but the incidence of HIV transmission between men and women has rapidly increased. In most other parts of the world, HIV is most commonly transmitted through heterosexual sex.
2. Contact with Infected Blood: Direct contact with HIV-infected blood occurs when people who use heroin or other injected drugs share hypodermic needles or syringes contaminated with infected blood. Sharing of contaminated needles among intravenous drug users has been a primary cause of HIV infection in parts of eastern Europe and central Asia.
Less frequently, HIV infection results when health professionals accidentally stick themselves with needles containing HIV-infected blood or expose an open cut to contaminated blood. Some cases of HIV transmission from transfusions of infected blood, blood components, and organ donations were reported in the 1980s. Since 1985 government regulations in the United States and Canada have required that all donated blood and body tissues be screened for the presence of HIV before being used in medical procedures. As a result of these regulations, HIV transmission caused by contaminated blood transfusion or organ donations is rare in North America. However, the problem continues to concern health officials in sub-Saharan Africa.
3. Mother-to-Child Transmission: HIV can be transmitted from an infected mother to her baby while the baby is still in the woman’s uterus or, more commonly, during childbirth. The virus can also be transmitted through the mother’s breast milk during breast-feeding. Mother-to-child transmission accounts for 90 percent of all cases of AIDS in children. Mother-to-child transmission is particularly prevalent in Africa.
4. Misperceptions About HIV Transmission: The routes of HIV transmission are well documented by scientists, but health officials continually grapple with people’s unfounded fears concerning the potential for HIV transmission by other means. HIV differs from other infectious viruses in that it dies quickly if exposed to the environment. No evidence has linked HIV transmission to casual contact with an infected person, such as a handshake, hugging, or kissing, or even sharing dishes or bathroom facilities. Studies have been unable to identify HIV transmission from modes common to other infectious diseases, such as an insect bite or inhaling virus-infected droplets from an infected person’s sneeze or cough.
SYMPTOMS OF AIDS
Without medical intervention, AIDS progresses along a typical course. Within one to three weeks after infection with HIV, most people experience flu-like symptoms, such as fever, sore throat, headache, skin rash, tender lymph nodes, and a vague feeling of discomfort. These symptoms last one to four weeks. During this phase, known as acute retroviral syndrome, HIV reproduces rapidly in the blood. The virus circulates in the blood throughout the body, particularly concentrating in organs of the lymphatic system.
The normal immune defenses against viral infections eventually activate to battle HIV in the body, reducing but not eliminating HIV in the blood. Infected individuals typically enter a prolonged asymptomatic phase, a symptom-free period that can last ten years or more. While persons who have HIV may remain in good health during this period, HIV continues to replicate, progressively destroying the immune system. Often an infected person remains unaware that he or she carries HIV and unknowingly transmits the virus to others during this phase of the infection.
When HIV infection reduces the number of CD4 cells from around 500 to 200 per microliter of blood, the infected individual enters an early symptomatic phase that may last a few months to several years. HIV-infected persons in this stage may experience a variety of symptoms that are not life-threatening but may be debilitating. These symptoms include extensive weight loss and fatigue (wasting syndrome), periodic fever, recurring diarrhea, and thrush, a fungal mouth infection. An early symptom of HIV infection in women is a recurring vaginal yeast infection. Unlike earlier stages of the disease, in this early symptomatic phase the symptoms that develop are severe enough to cause people to seek medical treatment. Many may first learn of their infection in this phase.
A. Opportunistic Infections
If CD4 cell levels drop below 200 cells per microliter of blood, the late symptomatic phase develops. This phase is characterized by the appearance of any of the opportunistic infections and rare cancers known as AIDS-defining conditions. The onset of these illnesses is a sign that an HIV-infected person has developed full-blown AIDS. Without medical treatment, this stage may last from several months to years. The cumulative effects of these illnesses usually cause death.
Often the first opportunistic infection to develop is pneumocystis pneumonia, a lung infection caused by the fungus Pneumocystis carinii. This fungus infects most people in childhood, settling harmlessly in the lungs where it is prevented from causing disease by the immune system. But once the immune system becomes weakened, the fungus can block the lungs from delivering sufficient oxygen to the blood. The lack of oxygen leads to severe shortness of breath accompanied by fever and a dry cough.
Often the first opportunistic infection to develop is pneumocystis pneumonia, a lung infection caused by the fungus Pneumocystis carinii. This fungus infects most people in childhood, settling harmlessly in the lungs where it is prevented from causing disease by the immune system. But once the immune system becomes weakened, the fungus can block the lungs from delivering sufficient oxygen to the blood. The lack of oxygen leads to severe shortness of breath accompanied by fever and a dry cough.
In addition to pneumocystis pneumonia, people with AIDS often develop other fungal infections. Up to 23 percent of people with AIDS become infected with fungi from the genus Cryptococcus, which cause meningitis, inflammation of the membranes that surround the brain. Infection by the fungus Histoplasma capsulatum affects up to 10 percent of people with AIDS, causing general weight loss, fever, and respiratory complications.
Tuberculosis, a severe lung infection caused by the bacterium Mycobacterium tuberculosis, typically becomes more severe in AIDS patients than in those with a healthy immune system. Between the 1950s and the late 1980s, tuberculosis was practically eradicated in North America. In the early 1990s, doctors became alarmed when incidence of the disease dramatically escalated. This resurgence was attributed to the increased susceptibility to tuberculosis of people infected with HIV. Infection by the bacterium Mycobacterium avium can cause fever, anemia, and diarrhea. Bacterial infections of the gastrointestinal tract contribute to wasting syndrome.
Opportunistic infections caused by viruses, especially members of the herpesvirus family, are common in people with AIDS. One of the herpesviruses, cytomegalovirus (CMV), infects the retina of the eye and can result in blindness. Another herpesvirus, Epstein-Barr virus (EBV), may cause certain types of blood cancers. Infections with herpes simplex virus (HSV) types 1 or 2 may result in sores around the mouth, genital area, or anus.
Many people with AIDS develop cancers. The destruction of CD4 cells impairs the immune functions that halt the development of cancer. Kaposi’s sarcoma is a cancer of blood vessels caused by a herpesvirus. This cancer produces purple lesions on the skin, which can spread to internal organs and cause death. B cell lymphoma affects certain cells of the lymphatic system that fight infection and perform other vital functions. Cervical cancer is more common in HIV-infected women than in women free from infection.
A variety of neurological disorders are common in the later stage of AIDS. Collectively called HIV-associated dementia, they develop when HIV or another microbial organism infects the brain. The infection produces degeneration of intellectual processes such as memory and, sometimes, problems with movement and coordination.
B. Symptoms in Children
HIV infection in children progresses more rapidly than in adults, most likely because a child’s immune system has not yet built up immunity to many infectious agents. The disease is particularly aggressive in infants—more than half of infants born with an HIV infection die before age two. Once a child is infected, the child’s undeveloped immune system cannot prevent the virus from multiplying quickly in the blood, and the disease progresses rapidly. In contrast, when an adult becomes infected with HIV, the adult’s immune system generally fights the infection. Therefore, HIV levels in adults remain lower for an extended period, delaying the progression of the disease.
Children develop many of the opportunistic infections that befall adults but also exhibit symptoms not observed in older patients. Among infants and children, HIV infection produces wasting syndrome and slows growth (generally referred to as failure to thrive). HIV typically infects a child’s brain early in the course of the disease, impairing intellectual development and coordination skills. While HIV can infect the brains of adults, it usually does so toward the later stages of the disease and produces different symptoms.
Children show a susceptibility to more bacterial and viral infections than adults. More than 20 percent of HIV-infected children develop serious, recurring bacterial infections, including meningitis and pneumonia. Some HIV-infected children suffer from repeated bouts of viral infections, such as chicken pox. Healthy children generally develop immunity to these viral illnesses after an initial infection.
DETECTING AND MONITORING HIV INFECTION
Since HIV was first identified as the cause of AIDS in 1983, a variety of tests have been developed that help diagnose HIV infection as well as determine how far the infection has progressed. Other tests can be used to screen donated blood, blood products, and body organs for the presence of HIV.
Doctors determine if HIV is present in the body by identifying HIV antibodies, specialized proteins created by the immune system to destroy HIV. The presence of these antibodies indicates HIV infection because they form in the body only when HIV is present. HIV antibodies form anywhere from five weeks to three months after HIV infection occurs, depending upon the individual’s immune system. The antibodies are produced continually throughout the course of the infection.The standard test to detect HIV antibodies in the blood is the enzyme-linked immunosorbent assay (ELISA). In this test, a blood sample is mixed with proteins from HIV. If the blood contains HIV antibodies, they attach to the HIV proteins, producing a telltale color change in the mixture. This test is highly reliable when performed two to three months after infection with HIV. The test is less reliable when used in the very early stage of HIV infection, before detectable levels of antibodies have had a chance to form. Doctors routinely confirm a positive result from an ELISA test by using the Western Blot test, which can detect lower levels of HIV antibodies. In this test a blood sample is applied to a paper strip containing HIV proteins. If HIV antibodies are present in the blood, they bind to the HIV proteins, producing a color change on the paper. The combination of the ELISA and the Western Blot test is more than 99.9 percent accurate in detecting HIV infection within 12 weeks following exposure.
Once tests confirm an HIV infection, doctors monitor the health of the infected person’s immune system by periodically measuring CD4 cell counts in the blood. The progressive loss of CD4 cells corresponds to a worsening of the disease as the immune system becomes increasingly impaired. Doctors also measure the viral load—the amount of the virus in the blood—using polymerase chain reaction (PCR) technology. PCR tests measure the level of viral ribonucleic acid (RNA), or HIV particles, in an infected person’s blood to determine how actively the virus is replicating and how fast the disease is progressing. Knowing the viral load helps doctors make decisions about the treatment and its effectiveness.
A modified ELISA test that detects p24 antigen, a protein produced by HIV, can determine if specific drug treatments are having a positive effect on a patient. Blood banks, plasma centers, clinical laboratories, private clinics, and public health departments also use this p24 antigen test to screen for the presence of HIV in blood, blood components, and organs before they are used in medical procedures.
DIAGNOSING AIDS
Physicians prefer to differentiate between people who have HIV infection and those who have AIDS. The Centers for Disease Control and Prevention (CDC), based in Atlanta, Georgia, recommends that physicians reserve the diagnosis of AIDS for HIV-infected individuals whose CD4 count falls below 200 cells per microliter of blood. A diagnosis of AIDS can also be made without confirmation of CD4 levels if someone who has no other reason for immune system damage develops an opportunistic disease.
TREATMENT
While no medical treatment cures AIDS, in the relatively short time since the disease was first recognized, new methods to treat the disease have developed rapidly. Health-care professionals focus on three areas of therapy for people living with HIV infection or AIDS: antiretroviral therapy using drugs that suppress HIV replication; medications and other treatments that fight the opportunistic infections and cancers that commonly accompany HIV infection; and support mechanisms that help people deal with the emotional repercussions as well as the practical considerations of living with a disabling, potentially fatal disease.
A. Antiretroviral Therapies
Understanding the specific steps in the HIV replication cycle is critical in order for scientists to develop drugs that attack vulnerable stages within the cycle. HIV belongs to a unique group of viruses known as retroviruses, so named because these viruses reverse the usual flow of genetic information within an infected cell. Most viruses store their genetic material in deoxyribonucleic acid (DNA), the double-helix structure that makes up genes. When a virus infects a cell, the viral DNA forms the template for the creation of messenger RNA, a type of ribonucleic acid. This messenger RNA directs the formation of specific proteins, and these proteins, in turn, build new virus particles (see Genetics). In HIV, however, genetic material is stored in two single-stranded RNA molecules. When HIV infects a cell, an enzyme called reverse transcriptase copies the genetic instructions in the virus’s RNA and moves it into the DNA. This movement of genetic information from RNA to DNA is the opposite of that which occurs in most cells during protein synthesis.
Another HIV enzyme, called integrase, helps the newly formed viral DNA to become part of the structure of the infected cell’s DNA. The viral DNA then forces the infected cell to manufacture HIV particles. A third HIV enzyme, called protease, packages these HIV particles into a complete and functional HIV virus. Over the last decade researchers have created a variety of drugs that block the action of some of the enzymes used in HIV replication. The main classes of drugs used against HIV are nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors.
Nucleoside analogues (also called nucleoside reverse transcriptase inhibitors (NRTIs)) impede the action of reverse transcriptase, the HIV enzyme that converts the virus’s genetic material into DNA. During this conversion process, these drugs incorporate themselves into the structure of the viral DNA, rendering the DNA useless and preventing it from instructing the infected cell to make additional HIV. The nucleoside analogue known as azidothymidine (AZT), which became available in 1987, was the first drug approved by the United States Food and Drug Administration (FDA) to treat AIDS. AZT slows HIV growth in the body, permitting an increase in the number of CD4 cells, which boosts the immune system. AZT also prevents transmission of HIV from an infected mother to her newborn. Since the introduction of AZT, additional nucleoside analogues have been developed, including didanosine (sold under the trade name Videx), zalcitabine (Hivid), stavudine (Zerit), lamivudine (Epivir), abacavir (Ziagen), and emtricitabine (Emtriva). These drugs are not particularly powerful when used alone, and often their benefits last for only 6 to 12 months. But when nucleoside analogues are used in combination with each other, they provide longer-lasting and more effective results.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs), introduced in 1996, use a different mechanism to block reverse transcriptase. These drugs bind directly to reverse transcriptase, preventing the enzyme from converting RNA to DNA. Three NNRTIs are available: nevirapine (Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva). NNRTIs work best when used in combination with nucleoside analogues.
The third group of antiviral drugs, called protease inhibitors, cripples protease, the enzyme vital to the formation of new HIV. When these drugs block protease, the defective HIV that forms is unable to infect new cells. Protease inhibitors are more powerful than nucleosides and NNRTIs, producing dramatic decreases in HIV levels in the blood. This reduced viral load, in turn, enables CD4 cell levels to skyrocket. The first protease inhibitor, saquinavir (Invirase), was approved in 1995. Since then other protease inhibitors have been approved, including ritonavir (Norvir), indinavir (Crixivan), nelfinavir (Viracept), amprenavir (Agenerase), tipranavir (Aptivus), and darunavir (Prezista).
A class of drugs known as fusion inhibitors became available in 2003. That year the FDA approved the use of enfuvirtide, sold under the brand name Fuzeon. Fusion inhibitors prevent the binding or fusion of HIV to CD4 cells. When used with other antiretroviral medicines, fusion inhibitors can reduce the amount of HIV in the blood and increase the number of CD4 cells. A related drug, called an entry inhibitor, was introduced in 2007 as maraviroc (Selzentry). It, too, is designed to prevent HIV from infecting CD4 cells.
1. Drug Resistance:When a single antiretroviral drug is used alone, its benefits last only a short time, as clinical studies of treatments with the drugs soon demonstrated. This short-term effectiveness is due to mutation, or changes in the genetic structure, of HIV that makes the virus resistant to the drug. The genetic material in HIV provides instructions for the manufacture of critical enzymes needed to replicate the virus. Scientists design antiretroviral drugs to impede the activity of these enzymes. If the virus mutates, the structure of the virus’s enzymes changes and the drugs no longer work against the enzymes or the virus.
Genes mutate during the course of viral replication, so the best way to prevent mutation is to halt replication. Studies have shown that the most effective treatment for halting HIV replication employs a combination of three drugs taken together—for instance, a combination of two nucleoside analogues with a protease inhibitor. This regimen, called triple therapy, maximizes drug potency while reducing the chance for drug resistance. The combination of three drugs is often referred to as an AIDS cocktail. In HIV-infected patients who have undergone triple therapy, the viral loads reduced significantly, sometimes to undetectable levels. Their CD4 cell count gradually increased, and they sustained good health with no complications. With this treatment, some patients who were near death were able to return to work and normal physical activity. Triple therapy was introduced in the United States in 1996. That year AIDS deaths in the United States decreased 26 percent, the first decrease since the beginning of the epidemic. In 1997 U.S. AIDS deaths decreased by 56 percent from the year before.
Despite its success, triple therapy has had some drawbacks. This multidrug therapy has been quite complicated, requiring patients to take anywhere from 2 to 20 pills a day on a specific schedule. Some drugs must be taken with food, and some cannot be taken at the same time as other pills. Even the most organized people find it difficult to take the pills correctly. Yet, just one or two lapses in treatment may cause the virus to develop resistance to the drug regimen.
In July 2006 the FDA approved a new three-drug combination that can be taken as a single pill once a day with or without food. Marketed under the name Atripla, the new drug combines the existing drugs Sustiva (the NNRTI efavirenz) and Truvada (the NRTIs emtricitabine and tenofovir) in a special formulation. The product is seen as a breakthrough in AIDS and HIV treatment for its simplicity and convenience. The once-daily pill form should help patients take the drugs on a regular, uninterrupted schedule that will not allow the HIV in their bodies to develop resistance to the drugs. The new pill could prove particularly useful in developing countries, where following complex regimens of different AIDS drugs is often impractical.
Many people find it difficult to deal with the unpleasant side effects produced by antiretroviral drugs. Common side effects include nausea, diarrhea, headache, fatigue, abdominal pain, kidney stones, anemia, and tingling or numbness in the hands and feet. Some patients may develop diabetes mellitus, while other patients develop collections of fat deposits in the abdomen or back, causing a noticeable change in body configuration. Some antiretroviral drugs produce an increase in blood fat levels, placing a patient at risk for heart attack or stroke. Some patients suffer more misery from the drug treatment than they do from the illnesses produced by HIV infection.
Perhaps the greatest drawback to triple therapy has been its cost, which has ranged from $10,000 to $12,000 a year. This high cost is well beyond the means of people with low incomes or those with limited health-care insurance. As a result, the most effective therapies currently available have remained beyond the reach of the majority of HIV-infected people worldwide.
2. Postexposure Prevention: Studies show that under certain circumstances, administering antiretroviral drugs within 24 hours (preferably within one to two hours) after exposure to HIV can protect a person from becoming infected with the virus. Although the effectiveness of postexposure antiretroviral therapy following sexual exposure to HIV remains uncertain, the CDC recommends that health-care personnel exposed to HIV infection from a needle stick or other accident take antiretroviral drugs.
3. Development of New Drugs: Scientists continue to develop more powerful HIV treatments that have fewer side effects and fewer resistance problems. Some drugs under investigation block the HIV enzyme integrase from inserting viral DNA into the infected cell. Other drugs prevent HIV from binding with a CD4 cell in the first place, thereby barring HIV entry into cells.
Some scientists focus on ways to fortify the immune system. A biological molecule called interleukin-2 shows promise in boosting the immune system’s arsenal of infection-fighting cells. Interleukin-2 stimulates the production of CD4 cells. If enough CD4 cells can be created, they may trigger other immune cell responses that can overpower HIV infection.
Some scientists focus on ways to fortify the immune system. A biological molecule called interleukin-2 shows promise in boosting the immune system’s arsenal of infection-fighting cells. Interleukin-2 stimulates the production of CD4 cells. If enough CD4 cells can be created, they may trigger other immune cell responses that can overpower HIV infection.
In other research, doctors hope to bolster the immune system with a vaccine (see Immunization). Most vaccines available today, including those that prevent measles or poliomyelitis, work by helping the body to create antibodies. Such vaccines mark specific infectious agents, such as the measles and polio viruses, for destruction. But many experts believe that an effective HIV vaccine will need to do more than just stimulate anti-HIV antibodies. Studies are underway to develop vaccines that also elevate the production of T cells in the immune system. Scientists hope that this dual approach will prime the immune system to attack HIV as soon as it appears in the body, perhaps containing the virus before it spreads through the body in a way that natural immune defenses cannot. The genetic variability of HIV frustrates efforts to develop a vaccine: A vaccine effective against one type of HIV may not work on a virus that has undergone genetic mutation.
B. Treatment of Opportunistic Infections
In addition to antiretroviral therapy to combat HIV infection, effective drug treatments are available to fight many of the medical complications that result from HIV infection. Doctors try to prevent infections before they begin to avoid taxing a patient’s weakened immune system unnecessarily. A doctor instructs an HIV-infected person on ways to avoid exposure to infectious agents that produce opportunistic infections common in people with a weakened immune system. Doctors usually prescribe more than one drug to forestall infections. For example, for those who have a history of pneumocystic pneumonia and a CD4 cell count of less than 200 cells per microliter, doctors may prescribe the antibiotics sulfamethoxazole and trimethoprim to prevent further bouts of pneumonia. Patients suffering from recurring thrush may be given the antifungal drug fluconazole for prolonged periods. For people with CD4 cell counts of less than 100 cells per microliter, doctors may prescribe clarithromycin or azithromycin to prevent Mycobacterium avium infections.
C. Support mechanisms
A person diagnosed with HIV infection faces many challenges, including choosing the best course of treatment, paying for health care, and providing for the needs of children in the family while ill. In addition to these practical considerations, people with HIV infection must cope with the emotional toll associated with the diagnosis of a potentially fatal illness. The social stigma that continues to surround a diagnosis of AIDS because of the disease’s prevalence among gay men or drug users causes many people to avoid telling family or friends about their illness. People with AIDS often feel incredibly lonely as they try to cope with a devastating illness on their own. Loneliness, anxiety, fear, anger, and other emotions often require as much attention as the medical illnesses common to HIV infection.
Since the AIDS epidemic began in the United States in 1981, grassroots organizations have been created to meet the medical and emotional needs of people who have AIDS and also to protect their civil rights. The Gay Men’s Health Crisis, founded in 1982, was the first nonprofit organization to provide medical, education, and advocacy services for people with AIDS. The Los Angeles Shanti Group was established in 1983 to provide emotional support and medical guidance to people with AIDS and other life-threatening illnesses. Activist organizations such as the AIDS Coalition to Unleash Power (ACT UP), founded in 1986, have been created to initiate faster change in public policies and to speed up the course of AIDS clinical research. American Foundation for AIDS Research (AMFAR), created in 1985, is the nation’s leading nonprofit organization dedicated to the support of AIDS research and the advocacy of fair and compassionate AIDS-related public policies. In Canada, the AIDS Committee of Toronto (ACT) was established in 1983 by community activists intent on fighting for the civil rights of people infected with HIV. As the AIDS epidemic grew, ACT expanded its mission to help people disabled by the disease and to spread health information to halt the spread of the disease. AIDS Vancouver (AV), also established in 1983, became the principal education, prevention, and support service organization for that city.
Counseling centers and churches provide individual or group counseling to help people with HIV infection or AIDS share their feelings, problems, and coping mechanisms with others. Family counseling can address the emotions of other family members who are disturbed by the diagnosis of HIV infection in another family member. Grief counseling also helps people who have lost friends or family members to AIDS.
PREVENTION OF AIDS
With a vaccine for AIDS years away and no cure on the horizon, experts believe that the most effective treatment for AIDS is to prevent HIV infection. Health officials focus public education programs on altering risky behaviors linked to HIV transmission, particularly unsafe sexual practices and needle-sharing by intravenous drug users. Safe-sex campaigns sponsored by health clinics, social centers, schools, and churches encourage sexual abstinence or monogamy (sexual relations with only one partner). Education programs instruct about the proper way to use condoms to provide a protective barrier against transmission of HIV during sexual intercourse. Needle-exchange programs, which provide clean needles to drug users, enable intravenous drug abusers to avoid sharing HIV-contaminated needles. Needle-exchange programs have been widely criticized because they seem to condone illicit drug use. However, numerous U.S. government-funded studies have indicated that such programs reduce HIV transmission without promoting greater drug use. To reduce the accidental transmission of HIV during medical procedures, both the United States and Canada have established strict guidelines for health-care settings, including the use of protective clothing and proper instrument disposal.
In the United States, the effectiveness of public education programs that target people at risk for HIV infection was well demonstrated in the gay community of San Francisco, California, in the 1980s. In 1982 and 1983, 6,000 to 8,000 people in San Francisco became infected with HIV. The gay community rallied to promote condom use and advocate monogamy through extensive education programs and public health advertisements geared for gay men. These public education programs were credited with reducing the number of gay men in San Francisco who became HIV infected. By 1993 the number of new infections declined to 1,000, and by 1999, fewer than 500 people were infected each year.
In the United States, the effectiveness of public education programs that target people at risk for HIV infection was well demonstrated in the gay community of San Francisco, California, in the 1980s. In 1982 and 1983, 6,000 to 8,000 people in San Francisco became infected with HIV. The gay community rallied to promote condom use and advocate monogamy through extensive education programs and public health advertisements geared for gay men. These public education programs were credited with reducing the number of gay men in San Francisco who became HIV infected. By 1993 the number of new infections declined to 1,000, and by 1999, fewer than 500 people were infected each year.
Public education about AIDS has also proven effective in other countries. Uganda was one of the first African countries to report cases of HIV infection. The first cases of AIDS were reported there in 1982, and by the late 1980s Uganda had one of the highest rates of HIV infection in the world. The Ugandan government was one of the first countries to set up a partnership with WHO to create a national AIDS control program called the AIDS Information Centre (AIC). The AIC has established extensive education programs promoting condom use and other methods to prevent HIV from spreading further. The program has also worked with community organizations to change social behaviors that increase the risk of HIV infection. The AIC promotes its message using innovative drama, song, and dance programs, a particularly effective communication method for African communities. AIC established confidential HIV testing services that provide same-day results and community counseling programs. As a result of Uganda’s quick response to the AIDS epidemic, the number of HIV infected people in that country declined significantly after 1993, during a time when most other African nations faced a frightening increase in the incidence of HIV infection.
Public health officials have learned that education programs that teach and reinforce safe behaviors through a series of meetings are more effective than one-time exposure to public-health information provided in a class lecture, magazine article, advertisement, or pamphlet. Education programs tailored to reflect specific ethnic and cultural preferences prove even more effective. For example, the Canadian Aboriginal AIDS Network creates HIV education programs that fight the common misperception among the indigenous peoples of Canada that AIDS is primarily a disease of white, affluent people. Among indigenous communities, the network promotes programs that use colloquial language to increase awareness about safe sex practices and needle use.
Another recently proposed approach to AIDS prevention is development of simple microbicidal creams or gels that women could use before sex to reduce the risk of HIV infection. Such topical anti-HIV products would be especially useful in developing countries where women may not have access to other forms of protection such as condoms. Currently, a number of different products are undergoing clinical trials in Africa.
Research conducted in Africa demonstrated that male circumcision could reduce by more than half a man’s risk of contracting AIDS through heterosexual intercourse. The findings were announced by the U.S. National Institutes of Health in 2006. They were not expected to affect AIDS prevention strategies in the United States, where most men are circumcised. However, adult circumcision could be a prevention strategy in developing countries where circumcision is less common. Male circumcision also lowers the risk of transmitting AIDS to women, but its effect on AIDS risk for men who have sex with men is not yet known.
SOCIAL PERSPECTIVES ON AIDS
Although new and effective AIDS drugs have brought hope to many HIV-infected persons, a number of social and ethical dilemmas still confront researchers and public-health officials. The latest combination drug therapies are far too expensive for infected persons in the developing world—particularly in sub-Saharan Africa, where the majority of AIDS deaths have occurred. In these regions, where the incidence of HIV infection has soared, the lack of access to drugs can be catastrophic.
A. Testing AIDS Drugs and Vaccines
AIDS research in the developing world has raised ethical questions pertaining to the clinical testing of new therapies and potential vaccines. For example, controversy erupted over 1997 clinical trials that tested a shorter course of AZT therapy in HIV-infected pregnant women in developing countries. Earlier studies had shown that administering AZT to pregnant women for up to six months prior to birth could cut mother-to-child transmission of HIV by up to two-thirds. The treatment’s $800 cost, however, made it too expensive for patients in developing nations.
The controversial 1997 clinical trials, which were conducted in Thailand and other regions in Asia and Africa, tested a shorter course of AZT treatment, costing only $50. Some pregnant women received AZT, while others received a placebo—a medically inactive substance often used in drug trials to help scientists determine the effectiveness of the drug under study. Ultimately the shorter course of AZT treatment proved to be successful and is now standard practice in a growing number of developing nations. However, at the time of the trials, critics charged that using a placebo on HIV-infected pregnant women—when AZT had already been shown to prevent mother-to-child transmission—was unethical and needlessly placed babies at fatal risk. Defenders of the studies countered that a placebo was necessary to accurately gauge the effectiveness of the AZT short-course treatment. Some critics speculated whether such a trial, while apparently acceptable in the developing nations of Asia and Africa, would ever have been viewed as ethical, or even permissible, in a developed nation like the United States.
Similar ethical questions surround the testing of AIDS vaccines in developing nations. Vaccines typically use weakened or killed HIV to spark antibody production. In some vaccines, these weakened or killed viruses have the potential to cause infection and disease. Critics have questioned whether it is ethical to place all the risk on test subjects in developing regions such as sub-Saharan Africa, where a person infected by a vaccine would have little or no access to medical care. At the same time, with AIDS causing up to 5,500 deaths a day in Africa, others feel that developing nations must pursue any medical avenue for stemming the epidemic and protecting people from the virus.
B. Economic Burden
For the struggling economies of some developing nations, AIDS has brought yet another burden: AIDS tends to kill young adults in the prime of their lives—the primary breadwinners and caregivers in families. According to figures released by the United Nations in 1999, AIDS has shortened the life expectancy in some African nations by an average of seven years. In Zimbabwe, life expectancy for adults declined from 61 years in 1993 to 38 in 2003, according to the World Health Organization (WHO). The next few decades may see average life expectance fall even lower in sub-Saharan Africa. Millions of children around the world have been orphaned by the AIDS epidemic. Those children who survive face poverty, a high risk of malnutrition and disease, and the absence of a family support structure.
In Africa, the disease has had a heavy impact on urban professionals—educated, skilled workers who play a critical role in the labor force of industries such as agriculture, education, transportation, and government. The decline in the skilled workforce has already damaged economic growth in Africa, and economists warn of disastrous consequences in the future.
C. Social stigma and discrimination
From the early days of the identification of AIDS, the disease has been powerfully linked to behaviors that are illegal (such as illicit drug use) or are considered immoral by many people (such as promiscuity and homosexuality). Consequently, a diagnosis of AIDS was a mark of disgrace, although medical research revealed that the disease follows well-defined modes of transmission that can affect any person. As the extent of the epidemic unfolded, misinformation about AIDS and how it is transmitted triggered widespread fear of contracting the disease. Some communities responded with hysteria that resulted in violence. In the United States, a Florida family with three HIV-positive sons who had become infected from blood transfusions were driven from their home when it was torched by an arsonist in 1987. In other communities, parents protested when HIV-infected children attended school. In many areas of the world, women in particular may face consequences if their HIV status is discovered. Reports indicate that many HIV-infected women are subject to domestic violence at the hands of their husbands—even if the husbands themselves are the source of infection. As a result, some women in developing nations fear being tested for HIV infection and cut themselves off from medical care and counseling.
In addition to social stigma, people infected with HIV must grapple with more immediate concerns—a daily struggle for basic medical care and other basic rights in the face of discrimination and fear because of their HIV status. In some places, nurses and other medical personnel who fear infection refuse to perform procedures on HIV-infected people. In 1998 the United States Supreme Court heard the case of Sidney Abbott, a young woman in Maine who sued dentist Randon Bragdon after he refused to treat her when he learned of her HIV-positive status. Basing its ruling on the Americans with Disabilities Act, the Supreme Court ruled in Bragdon v. Abbott that the woman’s HIV infection constituted a disability, even though she suffered from no disease symptoms. AIDS advocates expect this decision to protect the rights of many people with AIDS in the United States.
Some developing nations, such as Uganda, have met the AIDS crisis head-on, attempting to educate citizens and change high-risk behaviors in the population. However, other nations have been slow to even acknowledge the disease. In India, for example, the nation’s prime minister did not speak publicly about the dangers posed by the epidemic until 1999. In developed nations, some of the stigma attached to a diagnosis of AIDS has lessened in recent years, in part due to the admissions by public figures and celebrities, especially in the United States, that they were HIV-infected. The deaths from AIDS of actor Rock Hudson and tennis player Arthur Ashe, and the AIDS advocacy roles of basketball player Magic Johnson and Olympic diver Greg Louganis have personalized the disease and helped society come to terms with the enormity of the epidemic.
To some scientists, the AIDS epidemic signals a troubling trend in humanity’s future. Along with other deadly microbial threats of recent years—most notably Ebola virus, which has caused sporadic epidemics in Africa, and hantavirus, which broke out in the American Southwest in the early 1990s—AIDS is viewed by some as yet another in a series of emerging diseases that demonstrate how vulnerable humans are to newly encountered microbes. With population and land development increasing, humans have encroached farther into rain forests and other formerly wild areas, unleashing previously unknown disease agents. Meanwhile, global travel has become faster, more convenient, and more accessible to many people. Some scientists are worried by these trends, fearing the potential for an as-yet-unknown pathogen to arise and spread quickly and lethally around the globe.
The social, ethical, and economic effects of the AIDS epidemic are still being played out, and no one is entirely certain what the consequences will be. Despite the many grim facts of the AIDS epidemic, however, humanity is armed with proven, effective weapons against the disease: knowledge, education, prevention, and the ever-growing store of information about the virus’s actions.