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Human Immunodeficiency Virus Infection

by J. Allen McCutchan, MD, MSc

Human immunodeficiency virus (HIV) infection is a viral infection that progressively destroys certain white blood cells and can cause acquired immunodeficiency syndrome (AIDS).

  • HIV is transmitted through contact with a body fluid that contains the virus or cells infected with the virus.

  • HIV destroys certain types of white blood cells, weakening the body’s defenses against infections and cancers.

  • When people are first infected, symptoms of fever, rashes, swollen lymph nodes, and fatigue may last a few days to several weeks.

  • Many infected people remain well for more than a decade.

  • About half of untreated people become ill and develop AIDS, defined by the presence of serious infections and cancers, within about 10 years.

  • Eventually, most untreated people develop AIDS.

  • Blood tests to check for HIV antibody and to measure the amount of HIV virus can confirm the diagnosis.

  • HIV drugs (antiretroviral drugs), usually three or more taken together, can stop HIV from reproducing, strengthen the immune system, and thus make people less susceptible to infection, but the drugs cannot, with rare exceptions, eliminate HIV, which persists in an inactive form.

HIV infections may be caused by one of two retroviruses, HIV-1 or HIV-2. HIV-1 has caused a worldwide epidemic, but HIV-2 remains limited to West Africa.

HIV progressively destroys some types of white blood cells called CD4+ lymphocytes. Lymphocytes help defend the body against foreign cells, infectious organisms, and cancer (see Acquired Immunity : Lymphocytes). Thus, when HIV destroys CD4+ lymphocytes, people become susceptible to attack by many other infectious organisms. Many of the complications of HIV infection, including death, usually result from these other infections and not from HIV infection directly.

Acquired immunodeficiency syndrome (AIDS) is the most severe form of HIV infection. HIV infection is considered to be AIDS when at least one serious complicating illness develops or the number (count) of CD4+ lymphocytes decreases substantially.

HIV-1 originated in Central Africa during the first half of the 20th century when a closely related chimpanzee virus first infected people. The global spread of HIV-1 began in the late 1970s, and AIDS was first recognized in 1981. In 2011, more than 34 million people were living with HIV infection worldwide, 1.7 million died, and 2.5 million were newly infected. Most (95%) new infections occur in the developing world. More than half occur in women, and one in seven occur in children under 15 years old. In many African countries, fewer new infections are occurring compared with a decade ago, partly because of international efforts to provide treatment and strategies for prevention.

Did You Know...

  • No instance of HIV transmission through coughing, sneezing, or a mosquito bite has been documented.

Transmission of Infection

The transmission of HIV requires contact with a body fluid that contains the virus or cells infected with the virus. HIV can appear in nearly any body fluid, but transmission occurs mainly through blood, semen, vaginal fluids, and breast milk. Although tears, urine, and saliva may contain low concentrations of HIV, transmission through these fluids is extremely rare, if it occurs at all. HIV is not transmitted by casual contact (such as touching, holding, or dry kissing) or by close, nonsexual contact at work, school, or home. No case of HIV transmission has been traced to the coughing or sneezing of an infected person or to a mosquito bite. Transmission from an infected doctor or dentist to a patient is extremely rare.

HIV is usually transmitted in the following ways:

  • Sexual contact with an infected person, when the mucous membrane lining the mouth, vagina, penis, or rectum is exposed to body fluids such as semen or vaginal fluids that contain HIV, as occurs during unprotected sexual intercourse

  • Injection of contaminated blood, as can occur when needles are shared or a health care worker is accidentally pricked with an HIV-contaminated needle

  • Transfer from an infected mother to a child before birth, during birth, or after birth through the mother’s milk

  • Medical procedures, such as transfusion of blood that contains HIV, procedures done with inadequately sterilized instruments, or transplantation of an infected organ or tissues (see Overview of Transplantation)

HIV is more likely to be transmitted if skin or a mucous membrane is torn or damaged—even if minimally.

In the United States, Europe, and Australia, HIV has been transmitted mainly through male homosexual contact and the sharing of needles among people who inject drugs, but transmission through heterosexual contact accounts for about one fourth of cases. HIV transmission in Africa, the Caribbean, and Asia occurs primarily between heterosexuals, and HIV infection occurs equally among men and women. In the United States, fewer than 25% of adults who have HIV infection are women. Before 1992, most American women with HIV were infected by injecting drugs with contaminated needles, but now most are infected through heterosexual contact.

Through sexual activity

Risk of transmitting HIV is highest during vaginal or anal sex when a condom is not used or is used incorrectly. HIV transmission can also occur during oral sex, although transmission is less likely than during vaginal or anal sex.

Risk of HIV infection is increased when semen or vaginal fluids contain a large amount of HIV and/or when there are tears or sores, even small ones, in the skin or membranes lining the genitals, mouth, or rectum. Thus, transmission is much more likely during the following:

  • The first weeks after people are infected because at that time, the blood and body fluids contain very large amounts of HIV

  • Vigorous sexual activities that damage the skin or membranes lining the genitals, mouth, or rectum

  • Sexual intercourse when either partner has a genital herpes infection, syphilis, or another sexually transmitted disease (STD—see Overview of Sexually Transmitted Diseases) that can cause sores or tears in the skin or inflammation of the genitals

HIV (antiretroviral) drugs can reduce the amount of HIV in semen and vaginal fluids. Thus, these drugs can dramatically reduce likelihood of transmission.

What Is the Risk of HIV Transmission During Sexual Activities?

Risk

Activity

None (unless sores are present)

Dry kissing

Body-to-body rubbing and massage

Use of inserted sexual devices that are not shared with others

Stimulation of the genitals by a partner if there is no contact with semen or vaginal fluids

Bathing or showering together

Contact with feces or urine if the skin is intact

Theoretical (extremely low risk unless sores are present)

Wet kissing

Oral sex done to a male (fellatio) if ejaculation does not occur and a condom is used

Oral sex done to a female (cunnilingus) if a barrier is used

Oral-anal contact

Vaginal or anal penetration by a hand with or without a glove

Use of inserted sexual devices that are shared but are disinfected

Low

Oral sex done to an infected male with or without ingestion of semen if a condom is not used or is used incorrectly (risk is less if oral sex is done to an uninfected male by an infected person)

Oral sex done to a female if no barrier is used

Vaginal or anal intercourse if a condom is used correctly (for example, using only water-based lubricants and not spilling any semen)

Use of inserted sexual devices that are shared but are not disinfected

High

Vaginal or anal intercourse with or without ejaculation if a condom is not used or is used incorrectly


Through needles or other instruments

Health care workers who are accidentally pricked with an HIV-contaminated needle have about a 1 in 300 chance of contracting HIV unless they are treated as soon as possible after exposure. Such treatment reduces the chance of infection to less than 1 in 1500. The risk increases if the needle penetrates deeply or if the needle is hollow and contains HIV-contaminated blood (as with a needle used to draw blood or to inject street drugs) rather than simply being coated with blood (as with a needle used to stitch a cut).

Infected fluid splashing into the mouth or eyes has less than a 1 in 1,000 chance of causing infection.


From mother to child

HIV infection in a large number of women of childbearing age has led to an increase in HIV infection among children (see Human Immunodeficiency Virus (HIV) Infection in Children).

HIV infection can be transmitted from an infected mother to her child in the following ways:

  • To the fetus through the placenta

  • To the baby during passage through the birth canal

  • To the baby after birth through breast milk

If infected mothers are not treated, about 25 to 35% of their babies are likely to be infected at birth, and if they breastfeed, about another 10 to 15% of the babies are likely to be infected.

Treating infected women with HIV drugs can dramatically reduce the risk of transmission. Infected pregnant women should be treated during the 2nd and 3rd trimesters of pregnancy, during delivery, and during breastfeeding. Doing a cesarean delivery and treating the baby for several weeks after birth also reduce the risk. Infected mothers should not breastfeed if they live in countries where formula feeding is safe and affordable. However, in countries where infectious diseases and undernutrition are common causes of infant death and where safe, affordable infant formula is not available, the World Health Organization recommends that mothers breastfeed. In such cases, the protection provided by breastfeeding from potentially fatal infections may counterbalance the risk of HIV transmission.


Through blood transfusions or organ transplants

Rarely, HIV infection is transmitted through blood transfusions or organ transplants.

Since 1985 in most developed countries, all blood collected for transfusion is tested for HIV, and when possible, some blood products are treated with heat to eliminate the risk of HIV infection. The current risk of HIV infection from a single blood transfusion (which is carefully screened for HIV and other bloodborne viruses in most developed countries) is estimated to be less than 1 in about 2 million in the United States. However, in many developing countries, blood and blood products are not screened for HIV or are not screened as stringently. There, the risk remains substantial.

HIV has been transmitted when organs (kidneys, livers, hearts, pancreases, bone, and skin) from infected donors were unknowingly used as transplants. HIV transmission is unlikely to occur when corneas or certain specially treated tissues (such as bone) are transplanted.


Artificial insemination

HIV transmission is also possible when sperm from an infected donor is used to inseminate a woman. In the United States, measures have been taken to reduce this risk. Fresh semen samples are no longer used. Sperm from donors is frozen for 6 months or more. Then the donors are retested for HIV infection before the sperm is used.


Mechanism of Infection

Once in the body, HIV attaches to several types of white blood cells. The most important are certain helper T lymphocytes. Helper T lymphocytes activate and coordinate other cells of the immune system. On their surface, these lymphocytes have a receptor called CD4, which enables HIV to attach to them. Thus, these helper lymphocytes are designated as CD4+.

HIV stores its genetic information as ribonucleic acid (RNA). Once inside a CD4+ lymphocyte, the virus uses an enzyme called reverse transcriptase to make a copy of its RNA, but the copy is made as deoxyribonucleic acid (DNA). HIV mutates easily at this point because reverse transcriptase is prone to making errors during the conversion of HIV RNA to DNA. These mutations make HIV more difficult to control because the many mutations increase the chance of producing HIV that can resist attacks by the person’s immune system and/or antiretroviral drugs.

The HIV DNA copy is incorporated into the DNA of the infected lymphocyte. The lymphocyte’s own genetic machinery then reproduces (replicates) the HIV. Eventually, the lymphocyte is destroyed. Each infected lymphocyte produces thousands of new viruses, which infect other lymphocytes and destroy them as well. Within a few days or weeks, the blood and genital fluids contain a very large amount of HIV, and the number of CD4+ lymphocytes may be reduced substantially. Because the amount of HIV in blood and genital fluids is so large so soon after HIV infection, newly infected people transmit HIV to other people very easily.

Simplified Life Cycle of the Human Immunodeficiency Virus

Like all viruses, human immunodeficiency virus (HIV) reproduces (replicates) using the genetic machinery of the cell it infects, usually a CD4+ lymphocyte.

  • HIV first attaches to and penetrates its target cell.

  • HIV releases RNA, the genetic code of the virus, into the cell. For the virus to replicate, its RNA must be converted to DNA. The RNA is converted by an enzyme called reverse transcriptase (produced by HIV). HIV mutates easily at this point because reverse transcriptase is prone to errors during the conversion of viral RNA to DNA.

  • The viral DNA enters the cell’s nucleus.

  • With the help of an enzyme called integrase (also produced by HIV), the viral DNA becomes integrated with the cell’s DNA.

  • The DNA of the infected cell now produces viral RNA as well as proteins that are needed to assemble a new HIV.

  • A new virus is assembled from RNA and short pieces of protein.

  • The virus pushes (buds) through the membrane of the cell, wrapping itself in a fragment of the cell membrane and pinching off from the infected cell.

  • To be able to infect other cells, the budded virus must mature. It becomes mature when another HIV enzyme (HIV protease) cuts structural proteins in the virus, causing them to rearrange.

Drugs used to treat HIV infection were developed based on the life cycle of HIV. These drugs inhibit the three enzymes (reverse transcriptase, integrase, and protease) that the virus uses to replicate or to attach to and enter cells.

When HIV infection destroys CD4+ lymphocytes, it weakens the body’s immune system, which protects against many infections and cancers. This weakening is part of the reason that the body is unable to eliminate HIV infection once it has started. However, the immune system is able to mount some response. Within a month or two after infection, the body produces lymphocytes and antibodies that help lower the amount of HIV in the blood and keep the infection under control. For this reason, untreated HIV infection may cause no symptoms or only a few mild symptoms for an average of about 10 years (ranging from 2 to more than 15 years).

CD4 count

The number of CD4+ lymphocytes in blood (the CD4 count) helps determine how well the immune system can protect the body from infections and how severe the damage done by the HIV is. Most healthy people have a CD4 count of 500 to 1,000 cells per microliter of blood. Typically, the number of CD4+ lymphocytes is reduced during the first few months of infection. After about 3 to 6 months, the CD4 count stabilizes, but without treatment, it usually continues to decline at rates that vary from slow to rapid.

If the CD4 count falls below about 200 cells per microliter of blood, the immune system becomes less able to fight certain infections (such as Pneumocystis jirovecii pneumonia). Most of these infections are rare in healthy people. However, they are common among people with a weakened immune system. Such infections are called opportunistic infections because they take advantage of a weakened immune system. A count below about 50 cells per microliter of blood is particularly dangerous because additional opportunistic infections that can rapidly cause severe weight loss, blindness, or death commonly occur. These infections include cytomegalovirus infections (see Cytomegalovirus (CMV) Infection) and Mycobacterium avium complex infections (see Diseases Resembling Tuberculosis).


Viral load

The amount of HIV in the blood (specifically the number of copies of HIV RNA) is called the viral load. Viral load represents how quickly HIV is replicating. When people are first infected, the viral load increases rapidly. Then, after about 3 to 6 months, even without treatment, it drops to a lower level, which remains constant, called the set point. This level varies widely from person to person—from as little as a few hundred to over a million copies per microliter of blood. Viral load also indicates

  • How contagious the infection is

  • How fast the CD4 count is likely to decrease

  • How fast symptoms are likely to appear

The higher the set point, the more quickly the CD4 count decreases to the low levels (less than 200) that increase risk of opportunistic infections, even in people without symptoms.

During successful treatment, the viral load decreases to very low or undetectable levels (less than about 20 to 40 copies per microliter of blood). However, inactive (latent) HIV is still present within cells, and if treatment is stopped, HIV starts replicating and the viral load increases. An increase in the viral load during treatment may indicate that the HIV has developed resistance to drug treatment, that the person is not taking the prescribed drugs, or both.

Did You Know...

  • Some people are infected with HIV for years before they develop symptoms.


Symptoms

When initially infected, many people have no noticeable symptoms, but within 1 to 4 weeks, fever, rashes, swollen lymph nodes, fatigue, and a variety of less common symptoms develop in some people. Symptoms of initial (primary) HIV infection last from 3 to 14 days. The symptoms disappear, but lymph nodes often remain enlarged, felt as small, painless lumps in the neck, under the arms, or in the groin.

People can be infected with HIV infection for years—even several decades—before developing symptoms. However, the first symptoms may be those of AIDS. AIDS is defined as the development of very serious opportunistic infections or cancer—the ones that usually develop only in people with a CD4 count of less than 200 cells per microliter of blood. Before AIDS develops, many people feel well, although some develop a variety of symptoms such as weight loss, fatigue, recurring fever or diarrhea, and anemia.

The specific opportunistic infections and cancers that develop cause many of the symptoms. For example, thrush (an infection with the fungus Candida—see Candidiasis) may cause white patches in the mouth or vagina. Shingles (herpes zoster—see Shingles) may cause pain and a rash. More serious opportunistic infections may cause various symptoms depending on the organ affected:

  • Lungs: Fever, cough, or shortness of breath

  • Brain: Headache, weakness, loss of coordination, or deterioration of mental function

  • Digestive tract: Pain, diarrhea, or bleeding

HIV can also cause symptoms when it directly infects and damages organs such as the following:

  • Brain: Brain damage with memory loss, difficulty thinking and concentrating, or both, eventually resulting in dementia, as well as weakness, tremor, or difficulty walking

  • Kidneys: Kidney failure with swelling in the legs and face, fatigue, and changes in urination (more common in blacks than in whites), but often not until the infection is severe

  • Heart: Heart failure with shortness of breath, cough, wheezing, and fatigue (uncommon)

  • Genital organs: Decreased levels of sex hormones, which may cause fatigue and sexual dysfunction in men

HIV is probably directly responsible for a substantial loss of weight (AIDS wasting) in some people. Wasting in people with AIDS may also be caused by a series of infections or by an untreated, persistent digestive tract infection.

Kaposi sarcoma, a cancer caused by a sexually transmitted herpesvirus (see Kaposi Sarcoma), appears as painless, red to purple, raised patches on the skin. It occurs mainly in men who have sex with men.

Cancers of the immune system (lymphomas, typically non-Hodgkin lymphoma) may develop, sometimes first appearing in the brain. When the brain is affected, these cancers can cause weakness of an arm or a leg, headache, confusion, or personality changes.

Having AIDS increases the risk of other cancers. They include cancer of the cervix, anus, testes, and lungs as well as melanoma and other skin cancers. Homosexual men are prone to developing cancer of the rectum due to the same human papillomaviruses (HPV) that cause cancer of the cervix in women.

Usually, death is caused by the cumulative effects of opportunistic infections or cancers, wasting, and dementia.

Common Opportunistic Infections Associated with AIDS

Infection

Description

Symptoms

Candidal esophagitis

A yeast infection of the esophagus

Painful swallowing and burning in the chest

Pneumocystis jirovecii pneumonia

An infection of the lungs with the fungus Pneumocystis jiroveci i

Difficulty breathing, cough, and fever

Toxoplasmosis

Infection with the parasite Toxoplasma gondii, usually in the brain

Headache, confusion, lethargy, and seizures

Tuberculosis

Infection of the lungs and sometimes other organs with tuberculosis bacteria

Cough, fevers, night sweats, weight loss, and chest pain

Mycobacterium avium complex infection

Infection of the intestine or lungs with bacteria that resemble tuberculosis bacteria

Fever, weight loss, diarrhea, and cough

Cryptosporidiosis

Infection of the intestine with the parasite Cryptosporidium

Diarrhea, abdominal pain, and weight loss

Cryptococcal meningitis

Infection of the tissues covering the brain with the yeast Cryptococcus

Headache, fever, and confusion

Cytomegalovirus infection

Infection of the eyes or intestinal tract with cytomegalovirus

Eye: Clouding of vision or blindness

Intestinal tract: Diarrhea and weight loss

Diagnosis

Doctors usually ask about risk factors for HIV infection (such as occupational exposure, high-risk sexual activities, and use of injected street drugs) and about symptoms (such as fatigue, rashes, and weight loss). They do a physical examination to check for signs of opportunistic infections, such as swollen lymph nodes and white patches inside the mouth (indicating thrush), and for signs of Kaposi sarcoma of the skin or mouth. Early diagnosis is important because it makes early treatment possible. Early treatment enables infected people to live longer, be healthier, and be less likely to transmit HIV to other people.

Simple, accurate, screening tests that detect antibodies to HIV are available. Tests may be done using a blood sample in the laboratory or using a blood or saliva sample in the doctor’s office. Screening tests are done if doctors suspect HIV infection. In addition, doctors recommend that all adults and adolescents, particularly pregnant women, have a screening test regardless of what their risk appears to be. If people at low risk have a negative test result, the screening test is not repeated unless their risk status changes. For people at the highest risk, especially sexually active people who have several partners and who do not practice safe sex, testing should be repeated every 6 to 12 months.

If screening test results are positive, they are confirmed by a more accurate, specific test such as the Western blot. Often, these tests are not positive in the first weeks up to 2 months after initial HIV infection because antibodies to HIV are not yet being produced. Tests include the following:

  • Enzyme-linked immunosorbent assay (ELISA): This screening test is often used to detect HIV antibodies, but it requires complex equipment.

  • Rapid screening tests: These tests are being increasingly used to detect antibodies because they are quicker and simpler than ELISA, can be done in almost any setting, and provide immediate results.

  • Western blot: This test is usually done to confirm the diagnosis when screening test results are positive. It is more difficult to do than screening tests but is more accurate.

Other tests, such as tests to measure viral load (the amount of HIV RNA in the blood) or p24 antigen (which detects a protein in HIV), detect HIV in the blood sooner after the initial infection than tests for antibodies to HIV.

Anyone who is concerned about being infected with HIV can request to be tested. Such testing is confidential.

If HIV infection is diagnosed, blood tests should be done regularly to measure the CD4 count and viral load. If the CD4 count is low, people are more likely to develop serious infections and other complications of HIV such as certain cancers. Viral load helps predict how fast the CD4 count is likely to decrease over the next few years. These two measurements help doctors determine how soon to start antiretroviral drugs, what effects treatment is likely to have, and whether other drugs may be needed to prevent complicating infections. With successful treatment, the viral load falls to very low levels within weeks, and the CD4 count begins a slow recovery toward normal levels.

AIDS is diagnosed when the CD4 count falls below 200 cells per microliter of blood or when extreme wasting or certain serious opportunistic infections or cancers develop.

Prevention

At present, there is no effective HIV vaccine to prevent HIV infection or slow the progression of AIDS in people who are already infected.

Transmission of HIV through its most common routes—sexual contact or sharing of needles—is almost completely preventable. However, the measures required for prevention—sexual abstinence or consistent condom use (see How to Use a Condom) and access to clean needles—are sometimes personally or socially unpopular. Many people have difficulty changing their addictive or sexual behaviors, so they continue to put themselves at risk of HIV infection. Also, safe sex practices are not foolproof. For example, condoms can leak or break.

Condoms made of latex provide good protection against HIV (as well as other common sexually transmitted diseases), but they are not foolproof. Oil-based lubricants (such as petroleum jelly) should not be used because they may dissolve latex, reducing the condom's effectiveness.

Other measures can help. For men, circumcision, an inexpensive, safe procedure, reduces the risk of becoming infected during vaginal intercourse with an infected woman by about half. Whether circumcision reduces the risk of HIV infection in other circumstances is unclear.

Universal precautions

Because HIV is not transmitted through the air or by casual contact (such as touching, holding, or dry kissing), hospitals and clinics do not isolate HIV-infected people unless they have another contagious infection. Surfaces contaminated with HIV can easily be cleaned and disinfected because HIV is inactivated by heat and by common disinfectants such as hydrogen peroxide and alcohol. People who are likely to come into contact with blood or other body fluids at their job should wear protective latex gloves, masks, and eye shields. These precautions apply to body fluids from all people, not just those from people with HIV, and are thus called universal precautions. Universal precautions are taken for two reasons:

  • People with HIV may not know that they are infected

  • Viruses that cause other serious disorders (such as hepatitis B and C) can be transmitted by body fluids


Preventive treatment before exposure

Taking an antiretroviral drug before being exposed to HIV can reduce the risk of HIV infection. Such preventive treatment is called preexposure prophylaxis (PrEP). However, PrEP is expensive and is effective only if people take the drug every day that they are exposed to HIV. Thus, PrEP is recommended only for people who have a very high risk of infection. Such people include men who have sex with men and heterosexual men and women who have several sex partners and who are unable or unwilling to use condoms consistently.

People who use PrEP still need to use other methods to prevent HIV infection, including consistent use of condoms and not sharing needles to inject drugs.


Preventive treatment after exposure

People who have been exposed to HIV from a blood splash, needlestick, or sexual contact may reduce the chance of infection by taking antiretroviral drugs for 4 weeks. These drugs are more effective when they are started as soon as possible after the exposure. Taking two or three drugs is currently recommended.

Doctors and the person who was exposed typically decide together whether to use these preventive drugs. They base the decision on the estimated risk of infection and the possible side effects of the drugs. If they do not know whether the source is infected with HIV, they consider how likely the source is to be infected. However, even when the source of the exposure is known to be infected with HIV, the risk of infection after exposure varies, depending on the type of exposure. For example, risk from a blood splash is less than that from a needlestick.


Treatment

Antiretroviral drugs

Several classes of antiretroviral drugs are used together to treat HIV infection. These drugs block HIV from entering human cells or block the activity of one of the enzymes HIV needs to replicate inside human cells.

The drugs are grouped into classes based on how they act against HIV:

  • Reverse transcriptase inhibitors prevent HIV reverse transcriptase from converting HIV RNA into DNA. There are three types of these drugs: nucleoside, nucleotide, and non-nucleoside.

  • Protease inhibitors prevent protease from activating certain proteins inside newly produced viruses. The result is immature, defective HIV that does not infect new cells.

  • Entry (fusion) inhibitors prevent HIV from entering cells. To enter a human cell, HIV must bind to a CD4 receptor and one other receptor, such as the CCR-5 receptor. One type of entry inhibitor, CCR-5 inhibitors, blocks the CCR-5 receptor, preventing HIV from entering human cells.

  • Integrase inhibitors prevent HIV DNA from being integrated into human DNA.

These drugs prevent HIV from replicating in cells and dramatically reduce the amount of HIV in the blood over a few days to weeks. If replication is sufficiently slowed, the destruction of CD4+ lymphocytes by HIV is decreased and the CD4 count begins to increase. As a result, much of the damage to the immune system caused by HIV can be reversed. Doctors can detect this reversal by measuring the CD4 count, which begins to return toward normal levels over weeks to months. The CD4 count continues to increase for several years but at a slower rate.

Did You Know...

  • Drugs used to treat HIV infection help only if people take the drugs consistently and for the rest of their life.

HIV invariably develops resistance to any of these drugs if they are used alone. Resistance develops after a few days to several months of use, depending on the drug and the virus. HIV becomes resistant to drugs because of mutations that occur when it replicates. Treatment is most effective when three or more drugs are given in combination—usually one of the following combinations:

  • Three reverse transcriptase inhibitors (two nucleoside plus one non-nucleoside)

  • Two nucleoside reverse transcriptase inhibitors plus one or two protease inhibitors

These combinations of drugs are often referred to as combination antiretroviral therapy (CART). CART is used because

  • Combinations are more powerful than single drugs in reducing the amount of HIV in the blood.

  • Combinations help prevent the development of drug resistance.

  • Some HIV drugs (such as ritonavir) boost the blood levels of other HIV drugs (including most protease inhibitors) by slowing their removal from the body and thus increase their effectiveness.

CART can increase the CD4 count in HIV-infected people, thus strengthening their immune system and extending their life.

Combinations of antiretroviral drugs may have unpleasant and serious side effects. However, doctors can prevent many serious problems (such as anemia, hepatitis, kidney problems, and pancreatitis) by regularly examining the person and doing blood tests. The blood tests can detect side effects before they become serious and enable doctors to change antiretroviral drugs when needed. For most people, doctors can find a combination of drugs with minimal side effects.

Metabolism of fats may be disturbed, probably primarily by protease inhibitors. Fat accumulates in the abdomen and breasts of women (called central obesity), and it is lost from the face, arms, and legs. The body become less sensitive to insulin 's effects (called insulin resistance), and blood levels of cholesterol and triglycerides (two types of fat in the blood) are increased. This combination of problems (called metabolic syndrome—see Metabolic Syndrome) increases the risk of heart attacks and strokes.

Many drugs cause rashes (skin reactions). Some skin reactions can be very dangerous, especially if the drug causing the reaction is nevirapine or abacavir.

Nucleoside reverse transcriptase inhibitors can damage mitochondria (structures within cells that generate energy). Side effects include anemia, foot pain caused by nerve damage (neuropathy), liver damage that occasionally progresses to severe liver failure, and heart damage that can result in heart failure. Individual drugs differ in their tendency to cause these problems. When possible, doctors do not use the drugs with the most damaging side effects, such as stavudine and didanosine.

CART can cause bones to become less dense, resulting in osteopenia or osteoporosis (see Osteoporosis). Most people with these disorders do not have any symptoms, but they are at higher risk of fracturing a bone.

Because many drugs interact with HIV drugs, people should make sure their doctor knows which drugs they are taking. Also, other substances, such as grapefruit juice and the medicinal herb St. John’s wort, affect how the body uses some HIV drugs. Grapefruit juice increases the levels of saquinavir, increasing the risk of side effects. St. John's wort causes the body to process protease inhibitors and non-nucleoside reverse transcriptase inhibitors more quickly and thus makes them less effective.

When CART is successful, it sometimes causes the immune reconstitution inflammatory syndrome (IRIS). In this syndrome, symptoms of various infections worsen because immune responses improve (are reconstituted), increasing inflammation at sites of infection (see Defenses Against Infection : Inflammation). Symptoms sometimes worsen because parts of dead viruses persist, triggering immune responses. This syndrome typically occurs during the first few months of treatment and usually resolves on its own. If it does not, corticosteroids, given for a short time, are often effective. IRIS is more likely to cause symptoms and symptoms are more likely to be severe when CART is started soon after treatment of an opportunistic infection is started. Thus, for some (but not all) opportunistic infections, CART is delayed until treatment of the opportunistic infection has reduced or eliminated the infection.

Drug treatment is beneficial only if the drugs are taken on schedule. Missed doses allow the virus to replicate and develop resistance. Treatment cannot (with rare exceptions) eliminate the virus from the body, although the HIV level often decreases so much that it cannot be detected in blood or other fluids or tissues. An undetectable level is the goal of treatment. If treatment is stopped, the HIV level increases, and the CD4 count begins to fall.

The best time to start drug treatment is unclear, particularly in people who are not sick and whose CD4 count is still near normal. However, doctors agree that people with a CD4 count below 500 or a high viral load should be treated, even if they have no symptoms. Many doctors begin treatment when the CD4 count is above 500, particularly if the person is pregnant, has hepatitis B, or has kidney problems due to HIV infection.

Before starting a treatment regimen, people are taught about the necessity of taking drugs as directed, not skipping any doses, and taking the drugs for the rest of their life. Taking the drugs as directed for a life time is demanding. Some people skip doses or stop taking the drugs for a time (called a drug holiday). These practices are dangerous because they enable HIV to develop resistance to the drugs. Because taking HIV drugs irregularly often leads to drug resistance, health care practitioners try to make sure that people are both willing and able to adhere to the treatment regimen. To simplify the drug schedule and to help people take the drugs as directed, doctors often prescribe treatment that combines three or more drugs in one tablet that can be taken only once a day.

Drugs for HIV Infection

Drug*

Some Side Effects

Entry (fusion) inhibitors

Enfuvirtide

Painful rash at the injection site and allergic (hypersensitivity) reactions (including rash, fever, chills, nausea, and low blood pressure), numbness and tingling in the hands and feet (peripheral neuropathy), insomnia, and loss of appetite

Increased risk of pneumonia

Maraviroc (a CCR-5 inhibitor)

Inadequate blood flow (ischemia) to the heart or heart attacks

Integrase inhibitors

Elvitegravir

Nausea and diarrhea

Raltegravir

None

Non-nucleoside reverse transcriptase inhibitors

All of these drugs

Rash (occasionally severe or life threatening) and liver dysfunction

Efavirenz

Dizziness, sleepiness, nightmares, confusion, agitation, forgetfulness, and euphoria

Etravirine

Severe or life-threatening rashes

Nevirapine

Severe or life-threatening liver dysfunction and rashes, especially during the first 18 weeks of treatment

Rilpivirine

Depression, headache, and insomnia

Nucleoside and nucleotide reverse transcriptase inhibitors

All of these drugs

Lactic acidosis (buildup of lactic acid, a waste product of metabolism), which can be life threatening, and liver damage

Abacavir

A severe, sometimes fatal allergic reaction with fever, rash, nausea, vomiting, difficulty breathing, a sore throat, and cough

Loss of appetite, nausea, and vomiting

Didanosine (ddI)

Peripheral nerve damage, possibly life-threatening inflammation of the pancreas (pancreatitis), nausea, diarrhea, and an enlarged liver

Emtricitabine

Headache, nausea, diarrhea, and darkening of the skin (hyperpigmentation), especially on the palms and soles

Lamivudine (3TC)

Headache, fatigue, and peripheral nerve damage

Stavudine (d4T)

Peripheral nerve damage and loss of fat in the face, arms, and legs

Rarely, possibly life-threatening pancreas inflammation

Tenofovir

Mild to moderate diarrhea, nausea, vomiting, kidney damage, and flatulence

Zalcitabine (ddC)

Peripheral nerve damage, possibly life-threatening pancreas inflammation, and mouth sores

Zidovudine (AZT)

Anemia, susceptibility to infection (resulting from bone marrow damage), headache, insomnia, weakness, and muscle aches

Rarely, pancreas inflammation

Protease inhibitors

All of these drugs

Nausea, vomiting, diarrhea, abdominal discomfort, increased levels of blood sugar and cholesterol (common), increased abdominal fat, liver dysfunction, nail discoloration and deformity (ingrown nails), and a bleeding tendency (in people with hemophilia, bleeding)

Amprenavir

Rash

Darunavir

Headache, coldlike symptoms, severe rash, fever, and allergic reactions

Fosamprenavir

Rash

Indinavir

Kidney stones

Lopinavir

Mouth tingling and altered taste

Nelfinavir

Side effects of the drug class

Ritonavir

Mouth tingling and altered taste

Saquinavir

Side effects of the drug class

Tipranavir

Possibly life-threatening liver inflammation and bleeding within the brain

*All drugs, except enfuvirtide, are taken by mouth. Enfuvirtide is injected under the skin.

Side effects listed for the class of drug can occur when any drug in that class is used.


Prevention of opportunistic infections

If the CD4 count is low, drugs to prevent opportunistic infections are routinely prescribed.

  • If the CD4 count drops below 200 cells per microliter of blood or if people have thrush in their mouth and/or throat, the antibiotic trimethoprim-sulfamethoxazole is given to prevent Pneumocystis jirovecii pneumonia. This antibiotic also prevents toxoplasmosis, which can damage the brain.

  • If the CD4 count drops below 50 cells per microliter of blood, azithromycin taken weekly or clarithromycin taken daily may prevent Mycobacterium avium complex infections. If people cannot take either of these drugs, they are given rifabutin.

  • If cryptococcal meningitis or pneumonia, thrush, or a Candida infection in the vagina recurs, people may be given the antifungal drug fluconazole for a long time.

  • If herpes simplex infections of the mouth, lips, genitals, or rectum recur, people may require prolonged treatment with an antiviral drug (such as acyclovir).


Other drugs

Other drugs may help with the weakness, weight loss, and central obesity that may result from HIV infection:

  • Megestrol and dronabinol (a marijuana derivative) stimulate appetite. Many people find that natural marijuana is even more effective, and its use for this purpose has been legalized in a few states.

  • Anabolic steroids (such as testosterone) can help people regain muscle.

  • Growth hormone and tesamorelin (an injectable drug that releases growth hormone) reduce the central obesity that may result from HIV and its treatment.

If insulin resistance develops, drugs to increase sensitivity to insulin may help. If blood levels of cholesterol and triglycerides increase, lipid-lowering drugs (statins) can be used to lower them.

If testosterone levels are reduced in men, testosterone injections or patches on the skin can increase the levels.


Prognosis

Exposure to HIV does not always lead to infection, and some people who have had repeated exposures over many years remain uninfected. Moreover, many HIV-infected people remain well for more than a decade. A few HIV-infected, untreated people have remained well for over 20 years. Why some people become ill so much sooner than others is not fully understood, but a number of genetic factors appear to influence both susceptibility to infection and progression to AIDS after infection.

If infected people are not treated, AIDS develops in most, as follows:

  • For the first several years after infection: 1 to 2% each year

  • Each year thereafter: 5%

  • Within 10 to 11 years: 50%

  • Eventually: More than 95%, possibly all if they live long enough

However, with effective treatment, the HIV RNA level decreases to undetectable levels, CD4 counts increase dramatically, and people can continue to lead productive, active lives. The risk of illness and death decreases but remains higher than that of people who are of similar age and who are not infected with HIV. However, if people cannot tolerate or take drugs consistently, HIV infection and immune deficiency progresses, causing serious symptoms and complications.

Usually, HIV infection does not directly cause death. Instead, HIV infection leads to a substantial loss of weight (wasting), opportunistic infections, cancers, and other disorders, which then lead to death.

Cure has been thought to be impossible, although intensive research on how to eliminate all of the latent HIV from infected people continues.

End-of-Life Issues

Because death rarely occurs suddenly in people with AIDS, people usually have time to make plans for the kind of their health care they want if their condition worsens. Nonetheless, people should record such plans in a legal document early and should include clear instructions about the kind of care they want (see Advance Directives). Other legal documents, including powers of attorney and wills, should be prepared. These documents are particularly important for homosexual men because they may wish to protect the assets and rights (including visitation and decision-making) of their partners.

Near the end of life, many people have pain and other distressing symptoms (such as agitation) and usually lose their appetite. Hospice programs (see Hospice Care) are particularly equipped to deal with such problems. They can provide comprehensive support and care, which focuses on managing symptoms, helping dying people maintain their independence, and supporting their caregivers.

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • LEXIVA
  • EMTRIVA
  • VIRACEPT
  • VIREAD
  • INVIRASE
  • ISENTRESS
  • APTIVUS
  • CRIXIVAN
  • INTELENCE
  • FUZEON
  • ZERIT
  • ZIAGEN
  • RETROVIR
  • NORVIR
  • PREZISTA
  • EPIVIR
  • VIRAMUNE
  • SELZENTRY
  • EDURANT
  • SUSTIVA
  • VIDEX
  • ZOVIRAX
  • No US brand name
  • ZITHROMAX
  • MYCOBUTIN
  • BIAXIN
  • DIFLUCAN
  • MEGACE
  • DELATESTRYL
  • MARINOL