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Human Immunodeficiency Virus (HIV) Infection

by J. Allen McCutchan, MD, MSc

Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain infections and cancers. Initial infection may cause nonspecific febrile illness. Risk of subsequent manifestations—related to immunodeficiency—is proportional to the level of CD4+ lymphocytes. HIV can directly damage the brain, gonads, kidneys, and heart, causing cognitive impairment , hypogonadism, renal insufficiency, and cardiomyopathy. Manifestations range from asymptomatic carriage to AIDS, which is defined by serious opportunistic infections or cancers or a CD4 count of < 200/μL. HIV infection can be diagnosed by antibody, nucleic acid (HIV RNA), or antigen (p24) testing. Screening should be routinely offered to all adults and adolescents. Treatment aims to suppress HIV replication by using combinations of 3 or more drugs that inhibit HIV enzymes; treatment can restore immune function in most patients if suppression of replication is sustained.

(See also Human Immunodeficiency Virus (HIV) Infection in Infants and Children, the National Institute's of Health AIDSInfo web site , and the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America: Primary Care Guidelines for the Management of Persons Infected with HIV .)

Retroviruses are enveloped RNA viruses defined by their mechanism of replication via reverse transcription to produce DNA copies that integrate in the host cell genome. Several retroviruses, including human T-lymphotropic virus (see HTLV Infections), cause serious disorders in people.

AIDS is defined as HIV infection that leads to any of the disorders in clinical category B or C of HIV infection (see Clinical Categories of HIV Infection*) or a CD4+ T lymphocyte (helper cell—see T cells) count of < 200/μL. The disorders in categories B and C are

  • Serious opportunistic infections

  • Certain cancers, such as Kaposi sarcoma and non-Hodgkin lymphoma, to which defective cell-mediated immunity predisposes

  • Neurologic dysfunction

Clinical Categories of HIV Infection*


Disorder or Symptoms



Persistent generalized adenopathy

Symptoms of acute primary HIV infection


Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal that is persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe) or cervical carcinoma in situ

Constitutional symptoms, such as fever ( 38.5° C) or diarrhea lasting > 1 mo

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least 2 distinct episodes or > 1 dermatome

Immune thrombocytopenic purpura


Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

Peripheral neuropathy


Candidiasis of bronchi, trachea, lungs, or esophagus

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 mo duration)

Cytomegalovirus infection (other than that of the liver, spleen, or lymph nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

Herpes simplex with chronic ulcers (> 1 mo duration) or bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 mo duration)

Kaposi sarcoma

Lymphoma, Burkitt

Lymphoma, immunoblastic

Lymphoma of the brain, primary

Mycobacterium avium complex or M. kansasii infection, disseminated or extrapulmonary

M. tuberculosis infection, any site (pulmonary or extrapulmonary)

Mycobacterium infection by other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of the brain

Wasting syndrome due to HIV

*The CDC (1993) provided clinical categories of increasing severity based on opportunistic infections and tumors. Categories B and C represent AIDS-defining illnesses. Although categories correspond roughly with levels of immune dysfunction as measured by CD4 counts, they predict prognosis less well in patients receiving current treatments.

Added in the 1993 expansion of the AIDS surveillance case definition.

CDC = Centers for Disease Control and Prevention.

HIV-1 causes most HIV infections worldwide, but HIV-2 causes a substantial proportion of infections in parts of West Africa. In some areas of West Africa, both viruses are prevalent and may coinfect patients. HIV-2 appears to be less virulent than HIV-1.

HIV-1 originated in Central Africa in the first half of the 20th century, when a closely related chimpanzee virus first infected humans. Epidemic global spread began in the late 1970s, and AIDS was recognized in 1981. In 2011, > 34 million people were living with HIV worldwide, 1.7 million died, and 2.5 million were newly infected. Most new infections (95%) occur in the developing world, > 1/2 are in women, and 1/7 are in children < 15 yr. In many sub-Saharan African countries, incidence is declining markedly from the very high rates of a decade before.


Transmission of HIV requires contact with body fluids—specifically blood, semen, vaginal secretions, breast milk, saliva, or exudates from wounds or skin and mucosal lesions—that contain free HIV virions or infected cells. Transmission is more likely with the high levels of virions that are typical during primary infection, even when such infections are asymptomatic. Transmission by saliva or droplets produced by coughing or sneezing, although conceivable, is extremely unlikely. HIV is not transmitted by casual nonsexual contact as may occur at work, school, or home.

Transmission is usually by

  • Direct transfer of genital, rectal or oral fluids through sexual intercourse

  • Sharing of blood-contaminated needles

  • Childbirth

  • Breastfeeding

  • Medical procedures (eg, transfusions, exposure to contaminated instruments)

Sexual transmission

Sexual practices such as fellatio and cunnilingus appear to be relatively low risk but not absolutely safe (see Table: HIV Transmission Risk for Several Sexual Activities). Risk does not increase significantly if semen or vaginal secretions are swallowed. However, open sores in the mouth may increase risk.

The sexual practices with the highest risks are those that cause mucosal trauma, typically intercourse. Anal-receptive intercourse poses the highest risk. Mucous membrane inflammation facilitates HIV transmission; sexually transmitted diseases, such as gonorrhea, chlamydial infection, trichomoniasis, and especially those that cause ulceration (eg, chancroid, herpes, syphilis), increase the risk severalfold.

In heterosexuals, the estimated risk per coital act is about 1/1000; however, risk is increased in early and advanced stages of HIV infection when HIV concentrations in plasma and genital fluids are higher, in younger people, and in people with ulcerative genital diseases. Circumcision seems to reduce the risk of males acquiring HIV infection by about 50% by removing the penile mucosa (underside of foreskin), which is more susceptible to HIV infection than the keratinized, stratified squamous epithelium that covers the rest of the penis.

HIV Transmission Risk for Several Sexual Activities



None (unless sores are present)

Dry kissing

Body-to-body rubbing and massage

Using unshared inserted sexual devices

Genital stimulation by a partner but no contact with semen or vaginal fluids

Bathing or showering together

Contact with feces or urine if skin is intact

Theoretical (extremely low risk unless sores are present)

Wet kissing

Fellatio (oral sex done to a male) without ejaculation if a condom is used

Cunnilingus (oral sex done to a female) if a barrier is used

Oral-anal contact

Digital vaginal or anal penetration, with or without a glove

Use of shared but disinfected inserted sexual devices


Fellatio without a condom and with ejaculation

Cunnilingus if no barrier is used

Vaginal or anal intercourse if a condom is used correctly

Use of shared but not disinfected inserted sexual devices


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

Needle- and instrument-related transmission

Risk of transmission after skin penetration with a medical instrument contaminated with infected blood is on average about 1/300 without postexposure antiretroviral prophylaxis. Immediate prophylaxis probably reduces risk to < 1/1500. Risk appears to be higher if the wound is deep or if blood is inoculated (eg, with a contaminated hollow-bore needle). Risk is also increased with hollow-bore needles and with punctures of arteries of veins compared with solid needles or other penetrating objects coated with blood because larger volumes of blood may be transferred. Thus, sharing needles that have entered the veins of other injection drug users is a very high risk activity.

Risk of transmission from infected health care practitioners who take appropriate precautions is unclear but appears minimal. In the 1980s, one dentist transmitted HIV to 6 of his patients by unknown means. However, extensive investigations of patients cared for by other HIV-infected physicians, including surgeons, have uncovered few other cases.

Maternal transmission

HIV can be transmitted from mother to offspring transplacentally, perinatally, or via breast milk. Without treatment, risk of transmission at birth is about 25 to 35%. HIV is excreted in breast milk, and breastfeeding by untreated HIV-infected mothers may transmit HIV to about 10 to 15% of infants who had previously escaped infection. These rates can be reduced dramatically by treating HIV-positive mothers with antiretroviral drugs while they are pregnant, in labor, and breastfeeding. Because many HIV-positive pregnant women are treated or take prophylactic drugs, the incidence of AIDS in children is decreasing in many countries (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children).

Transfusion- and transplant-related transmission

Screening of blood donors with tests for both antibody to HIV and HIV RNA has minimized risk of transmission via transfusion. Current risk of transmitting HIV via blood transfusion is probably < 1/2,000,000 per unit transfused in the US. However, in many developing countries, where blood and blood products are not screened for HIV, the risk of transfusion-transmitted HIV infection remains high.

Rarely, HIV has been transmitted via transplantation of organs from HIV-seropositive donors. Infection has developed in recipients of kidney, liver, heart, pancreas, bone, and skin—all of which contain blood—but screening for HIV greatly reduces risk of transmission. HIV transmission is even more unlikely from transplantation of cornea, ethanol-treated and lyophilized bone, fresh-frozen bone without marrow, lyophilized tendon or fascia, or lyophilized and irradiated dura mater. HIV transmission is possible via artificial insemination using sperm from HIV-positive donors.


HIV has spread in 2 epidemiologically distinct patterns:

  • Male homosexual intercourse or contact with infected blood (eg, through sharing needles in injection drug users; before effective screening of donors, through transfusions)

  • Heterosexual intercourse (affecting men and women about equally)

In most countries, both patterns occur, but the first pattern usually predominates in developed countries; the second pattern predominates in Africa, South America, and southern Asia. In areas where heterosexual transmission is dominant, HIV infection follows routes of trade, transportation, and economic migration to cities and spreads secondarily to rural areas. In Africa, particularly southern Africa, the HIV epidemic has killed tens of millions of young adults, creating millions of orphans. Factors that perpetuate spread include poverty, poor education, and deficient systems of medical care that do not provide access to antiretroviral drugs; however, through international efforts, an estimated 10 million patients have been treated, dramatically reducing deaths and transmission in many countries.

Many opportunistic infections that complicate HIV are reactivations of latent infections. Thus, epidemiologic factors that determine the prevalence of latent infections also influence risk of specific opportunistic infections. In many developing countries, prevalence of latent TB and toxoplasmosis in the general population is higher than that in developed countries. Dramatic increases in reactivated TB and toxoplasmic encephalitis have followed the epidemic of HIV-induced immunosuppression in these countries. Similarly in the US, incidence of coccidioidomycosis, common in the Southwest, and histoplasmosis, common in the Midwest, has increased because of HIV infection. Human herpesvirus 8 infection, which causes Kaposi sarcoma, is common among homosexual and bisexual men but uncommon among other HIV patients in the US and Europe. Thus, in the US, > 90% of AIDS patients who have developed Kaposi sarcoma are homosexual or bisexual men.


HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see see Figure: Simplified HIV life cycle.). After attachment, HIV RNA and several HIV-encoded enzymes are released into the host cell. Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations. These mutations facilitate the generation of HIV that can resist control by the host’s immune system and by antiretroviral drugs. Proviral DNA enters the host cell’s nucleus and is integrated into the host DNA in a process that involves integrase, another HIV enzyme. With each cell division, the integrated proviral DNA is duplicated along with the host DNA. Subsequently, the proviral HIV DNA can be transcribed to HIV RNA and translated to HIV proteins, such as the envelope glycoproteins 41 and 120. These HIV proteins are assembled into HIV virions at the host cell inner membrane and budded from the cell surface within an envelop of modified human cell membrane. Each host cell may produce thousands of virions. After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a mature, infectious virion.

Simplified HIV life cycle.

HIV attaches to and penetrates host T cells, then releases HIV RNA and enzymes into the host cell. HIV reverse transcriptase copies viral RNA as proviral DNA. Proviral DNA enters the host cell’s nucleus, and HIV integrase facilitates the proviral DNA’s integration into the host’s DNA. The host cell then produces HIV RNA and HIV proteins. HIV proteins are assembled into HIV virions and budded from the cell surface. HIV protease cleaves viral proteins, converting the immature virion to a mature, infectious virion.

Infected CD4+ lymphocytes produce > 98% of plasma HIV virions. A subset of infected CD4+ lymphocytes constitutes a reservoir of HIV that can reactivate (eg, if antiviral treatment is stopped). Virions have a plasma half-life of about 6 h. In moderate to heavy HIV infection, about 10 8 to 10 9 virions are created and removed daily. The high volume of HIV replication and high frequency of transcription errors by HIV reverse transcriptase result in many mutations, increasing the chance of producing strains resistant to host immunity and drugs.

Immune system

Two main consequences of HIV infection are

  • Damage to the immune system, specifically depletion of CD4+ lymphocytes

  • Immune activation

CD4+ lymphocytes are involved in cell-mediated and, to a lesser extent, humoral immunity. CD4+ depletion may result from the following:

  • Direct cytotoxic effects of HIV replication

  • Cell-mediated immune cytotoxicity

  • Thymic damage that impairs lymphocyte production

Infected CD4+ lymphocytes have a half-life of about 2 days, which is much shorter than that of uninfected CD4+ cells. Rates of CD4+ lymphocyte destruction correlate with plasma HIV level. Typically, during the initial or primary infection, HIV levels are highest (> 10 6 copies/mL), and the CD4 count drops rapidly. The normal CD4 count is about 750/μL, and immunity is minimally affected if the count is > 350/μL. If the count drops below about 200/μL, loss of cell-mediated immunity allows a variety of opportunistic pathogens to reactivate from latent states and cause clinical disease.

The humoral immune system is also affected. Hyperplasia of B cells in lymph nodes causes lymphadenopathy, and secretion of antibodies to previously encountered antigens increases, often leading to hyperglobulinemia. Total antibody levels (especially IgG and IgA) and titers against previously encountered antigens may be unusually high. However, antibody response to new antigens (eg, in vaccines) decreases as the CD4 count decreases.

Abnormal elevation of immune activation may be caused in part by absorption of components of bowel bacteria. Immune activation contributes to CD4+ depletion and immunosupression by mechanisms that remain unclear

Other tissues

HIV also infects nonlymphoid monocytic cells (eg, dendritic cells in the skin, macrophages, brain microglia) and cells of the brain, genital tract, heart, and kidneys, causing disease in the corresponding organ systems. HIV strains in several compartments, such as the nervous system (brain and CSF) and genital tract (semen), can be genetically distinct from those in plasma, suggesting that they have been selected by or have adapted to these anatomic compartments. Thus, HIV levels and resistance patterns in these compartments may vary independently from those in plasma.

Disease progression

During the first few weeks of primary infection, there are humoral and cellular immune responses. Antibodies to HIV are usually measurable within a few weeks after primary infection; however, antibodies cannot fully control HIV infection because mutated forms of HIV that are not controlled by the patient’s current anti-HIV antibodies are generated. Cell-mediated immunity is a more important means of controlling the high levels of viremia (usually over 10 6 copies/mL) at first. But rapid mutation of viral antigens that are targeted by lymphocyte-mediated cytotoxicity subvert control of HIV in all but a small percentage of patients. Plasma HIV virion levels, expressed as number of HIV RNA copies/mL, stabilize after about 6 mo at a level (set point) that varies widely among patients but averages 30,000 to 100,000/mL (4.2 to 5 log 10 /mL). The higher this set point, the more quickly the CD4 count decreases to a level that seriously impairs immunity (< 200/μL) and results in the opportunistic infections and cancers that define AIDS.

Risk and severity of opportunistic infections, AIDS, and AIDS-related cancers are determined by 2 factors:

  • CD4 count

  • Exposure to potentially opportunistic pathogens

Risk of specific opportunistic infections increases below threshold CD4 counts of about 200/μL for some infections and 50/μL for others. For example, risk of Pneumocystis jirovecii pneumonia, toxoplasmic encephalitis, and cryptococcal meningitis rises when the CD4 count is < 200/μL; cytomegalovirus (CMV) and Mycobacterium avium complex (MAC) infections are a risk when the CD4 count is < 50/μL. For every 3-fold (0.5 log 10 ) increase in plasma HIV RNA in untreated patients, risk of progression to AIDS or death over the next 2 to 3 yr increases about 50%.

Without treatment, risk of progression to AIDS is about 1 to 2%/yr in the first 2 to 3 yr of infection and about 5 to 6%/yr thereafter. Eventually, AIDS almost invariably develops in untreated patients.

Symptoms and Signs

Initially, primary HIV infection may be asymptomatic or cause transient nonspecific symptoms (acute retroviral syndrome). Acute retroviral syndrome usually begins within 1 to 4 wk of infection and usually lasts 3 to 14 days. Symptoms and signs are often mistaken for infectious mononucleosis or benign, nonspecific viral syndromes and may include fever, malaise, fatigue, several types of dermatitis, arthralgias, generalized lymphadenopathy, and septic meningitis.

After the first symptoms disappear, most patients, even without treatment, have no symptoms or only a few, mild, intermittent, nonspecific symptoms for a highly variable time period (2 to 15 yr).

Symptoms during this relatively asymptomatic period may result from HIV directly or from opportunistic infections. The following are most common:

  • Lymphadenopathy

  • White plaques due to oral candidiasis

  • Herpes zoster

  • Diarrhea

  • Fatigue

  • Fever with intermittent sweats

Asymptomatic, mild-to-moderate cytopenias (eg, leukopenia, anemia, thrombocytopenia) are also common. Some patients experience progressive wasting (which may be related to anorexia and increased catabolism due to infections) and low-grade fevers or diarrhea.

When the CD4 count drops to < 200/μL, nonspecific symptoms may worsen and a succession of AIDS-defining illnesses (those in category B or C of Clinical Categories of HIV Infection*) develop. Evaluation may detect infection by Mycobacterium sp, P. jirovecii, Cryptococcus neoformans, or other fungi. Infections that also occur in the general population but suggest AIDS if they are unusually severe or frequently recur include herpes zoster, herpes simplex, vaginal candidiasis, and Salmonella septicemia. In patients with HIV infection, certain syndromes are common and may require different considerations (see Common Manifestations of HIV Infection by Organ System). Some patients present with cancers (eg, Kaposi sarcoma, B-cell lymphomas) that occur more frequently, are unusually severe, or have unique features in patients with HIV infection (see Cancers Common in HIV-Infected Patients). In other patients, neurologic dysfunction may occur.

Common Manifestations of HIV Infection by Organ System



Diagnostic Evaluation




Mild to severe cognitive impairment with or without motor deficits

Direct virus-induced brain damage

HIV RNA level in CSF

CT or MRI to check for brain atrophy (nonspecific)

Antiretroviral drugs, which may reverse damage and improve function, although low levels of cognitive dysfunction commonly persist, even in treated patients

Progression to dementia uncommon in treated patients

Ascending paralysis

Guillain-Barré syndrome or CMV polyradiculopathy

Spinal cord MRI

CSF testing

Treatment of CMV polyradiculopathy

Supportive care for Guillain-Barré syndrome

Neutrophilic pleocytosis in patients with CMV polyradiculopathy, possibly simulating bacterial meningitis

Acute or subacute focal encephalitis (see Encephalitis)

Toxoplasma gondii

CT or MRI to check for ring-enhancing lesions, especially near basal ganglia

Antibody testing of CSF (sensitive but not specific)

PCR testing to check for T. gondii DNA in CSF

Brain biopsy (rarely indicated)

Pyrimethamine, folinic acid, sulfadiazine, and possibly trimethoprim/sulfamethoxazole (clindamycin if allergic to sulfa—see Treatment)

Often lifelong maintenance therapy

Primary prophylaxis with clindamycin and pyrimethamine or trimethoprim/ sulfamethoxazole (as for Pneumocystis pneumonia) indicated for patients with a CD4 count of < 100/μL and previous toxoplasmosis or positive antibodies; can be stopped if CD4 counts increase to >200/μL for ≥ 3 mo in response to antiretroviral therapy

Subacute encephalitis

Less often, herpes simplex virus or varicella-zoster virus


Response to treatment

Antiviral drugs

With CMV, often delirium, cranial nerve palsies, myoclonus, seizures, and progressively impaired consciousness at presentation

Often responds rapidly to treatment

Myelitis or polyradiculopathy (see Acute Transverse Myelitis)


Spinal cord MRI


Antiviral drugs (see Antiviral drugs)

Simulates Guillain-Barré syndrome

Progressive encephalitis of white matter only

Progressive multifocal leukoencephalopathy due to reactivation of latent JC virus infection (see Progressive Multifocal Leukoencephalopathy (PML))


Brain MRI

CSF testing

Antiretroviral drugs

Usually fatal within a few months

May respond to antiretroviral drugs

Subacute meningitis

Cryptococcus, Histoplasma, or Mycobacterium tuberculosis


CSF stains, antigen tests, and cultures

Treatment of cause

Outcomes improved by early treatment

Peripheral neuropathy (see Peripheral Neuropathy)

Direct effects of HIV or CMV or antiviral toxicity


Sensory and motor testing

Treatment of cause or withdrawal of toxic drugs

Very common

Not quickly reversible




Direct retinoscopy

Specific anti-CMV drugs (see Cytomegalovirus (CMV) Infection : Treatment)

Requires examination by specialist



Direct viral damage to cardiac myocytes


Antiretroviral drugs

Symptoms of heart failure


Nephrotic syndrome or renal insufficiency

Direct viral damage, resulting in focal glomerulosclerosis

Renal biopsy

Antiretroviral drugs or ACE inhibitors possibly useful

Increased incidence in African Americans and patients with a low CD4 count


Oral candidiasis (see Candidiasis (Invasive))

Immunosuppression by HIV


Systemic antifungals (see Antifungal Drugs)

Possibly painless in early stages

Intraoral ulcers

Herpes simplex virus or aphthous stomatitis

Examination ( Stomatitis : Evaluation)

For aphthous ulcers, intralesional or systemic corticosteroids and systemic montelukast and thalidomide ( Stomatitis : Treatment)

For herpes, acyclovir

May be severe and result in undernutrition

Periodontal disease

Mixed oral bacterial flora


Improved hygiene and nutrition


May be severe, with bleeding, swelling, and tooth loss

Painless intraoral mass

Kaposi sarcoma or lymphoma


Treatment of neoplasm

Painless white filiform patches on the sides of the tongue (oral hairy leukoplakia)

Epstein-Barr virus



Usually asymptomatic



Candidiasis, CMV, or herpes simplex virus

Esophagoscopy with biopsy of ulcers

Treatment of cause

Dysphagia, anorexia

Gastroenteritis or colitis

Intestinal Salmonella, MAC, Cryptosporidium, CMV, microsporidia, Cystoisospora (Isospora) belli, or Clostridium difficile

Cultures and stains of stools or biopsy, but determination of cause possibly difficult

Supportive treatment of cause and symptoms

Diarrhea, weight loss, abdominal cramping

Cholecystitis or cholangitis

CMV, Cryptosporidium, or microsporidia

Ultrasonography or endoscopy

Treatment of CMV

Antiretrovirals for Cryptosporidium

Possibly pain or obstruction

Anal, rectal, and perirectal lesions

Herpes simplex virus, human papillomavirus, or anal cancer

Possibly multiple causes


Gram staining and culture


Treatment of cause

High incidence in homosexual men who are infected with human papillomavirus via anal receptive sexual intercourse

Hepatocellular damage due to hepatitis viruses, opportunistic infections, or antiviral toxicity

TB, MAC, CMV, or peliosis (bartonellosis)

Chronic hepatitis B or C may be worsened by HIV

Differentiation from hepatitis due to antiretroviral or other drugs

Liver biopsy sometimes necessary

Treatment of cause

Symptoms of hepatitis (eg, anorexia, nausea, vomiting, jaundice)


Herpes zoster

Varicella-zoster virus

Clinical evaluation (see Herpes Zoster : Diagnosis)

Acyclovir or related drugs


Possible prodrome of mild to severe pain or tingling before skin lesions

Herpes simplex ulcers

Herpes simplex virus

Usually clinical evaluation (see Herpes Simplex Virus (HSV) Infections : Diagnosis)

Antiviral drugs if lesions are severe, extensive, persistent, or disseminated

Atypical lesions of herpes simplex that are extensive, severe, or persistent


Sarcoptes scabiei

Possibly severe hyperkeratotic lesions

Violaceous or red papules or nodules

Kaposi sarcoma or bartonellosis


Treatment of cause

Centrally umbilicated skin lesions

Cryptococcosis or molluscum contagiosum

May be the presenting sign of cryptococcemia


Subacute (occasionally acute) pneumonia

Mycobacteria, fungi such as P. jirovecii, C. neoformans, H. capsulatum, Coccidioides immitis, or Aspergillus

Pulse oximetry

Chest x-ray

Skin tests (sometimes false-negative because of anergy)

Bronchoscopy with special stains and cultures of bronchial lavage specimens sometimes necessary

Treatment of cause

Possibly cough, tachypnea, and chest discomfort at presentation

Mild hypoxia or increased alveolar-arterial O 2 gradient possibly occurring before evidence of pneumonia on x-ray

Acute (occasionally subacute) pneumonia

Typical bacterial pathogens or Haemophilus, Pseudomonas, Nocardia, or Rhodococcus

In patients with known or suspected HIV and pneumonia, exclusion of opportunistic or unusual pathogens

Treatment of cause

Possibly cough, tachypnea, and chest discomfort at presentation


Candida or herpes simplex virus

Treatment of cause

Possibly cough, tachypnea, and chest discomfort at presentation

Subacute or chronic pneumonia or mediastinal adenopathy

Kaposi sarcoma or B-cell lymphoma

Chest CT


Treatment of cause

Possibly cough, tachypnea, and chest discomfort at presentation


Sepsis and septic shock due to nosocomial gram-negative bacillary and staphylococcal infections, disseminated opportunistic infections

Gram-negative bacilli, Staphylococcus aureus, Candida, Salmonella, M. tuberculosis, MAC, or H. capsulatum

Blood cultures

Bone marrow examination

Treatment of cause


Vaginal candidiasis


Possibly increased in severity or recurrent

Pelvic inflammatory disease

Neisseria gonorrhoeae, Chlamydia trachomatis, or other usual pathogens

Possibly increased in severity, atypical, and difficult to treat




HIV-induced bone marrow suppression

Immune-mediated peripheral destruction

Anemia of chronic disease

Infections, particularly human parvovirus B-19, disseminated MAC, or histoplasmosis


For parvovirus B19 infection, bone marrow examination (to check for multinucleated erythroblasts) or serum or bone marrow PCR.

Treatment of cause

Transfusion as needed

Erythropoietin for anemia due to antineoplastic drugs or zidovudine if severity warrants transfusion and erythropoietin level is < 500 mU/L

IVIG for parvovirus

With parvovirus, sometimes acute severe anemia


Immune thrombocytopenia (see Immune Thrombocytopenia (ITP)), drug toxicity, HIV-induced marrow suppression, immune-mediated peripheral destruction, infections, or cancer

CBC, clotting tests, PTT, peripheral smear, bone marrow biopsy, or von Willebrand factor measurement

Antiretroviral drugs

IVIG for bleeding or preoperatively

Possibly anti-Rho (D) IgG, vincristine, danazol, or interferon

If severe and intractable, splenectomy

Often asymptomatic and may occur in otherwise asymptomatic HIV infection


HIV-induced bone marrow suppression, immune-mediated peripheral destruction, infections, cancer, or drug toxicity

For severe neutropenia (< 500/μL) plus fever, immediate broad-spectrum antibiotics (see Neutropenia : Treatment).

If drug-induced, granulocyte or granulocyte-macrophage colony-stimulating factors

CMV = cytomegalovirus; IVIG = IV immune globulin; MAC = Mycobacterium avium complex.


  • HIV antibody testing

  • Nucleic acid amplification assays to determine HIV RNA level (viral load)

HIV infection is suspected in patients with persistent, unexplained, generalized adenopathy or any of the disorders in category B or C (see Clinical Categories of HIV Infection*). It may also be suspected in high-risk patients with symptoms that could represent acute primary HIV infection.

Detection of antibodies to HIV is sensitive and specific except during the first few weeks after infection. Enzyme-linked immunosorbent assay (ELISA) to detect HIV antibodies is highly sensitive, but rarely, results are false-positive. Positive ELISA results are therefore confirmed with a more specific test such as Western blot. However, these tests have drawbacks:

  • ELISA requires complex equipment.

  • Western blot requires well-trained technicians and is expensive.

  • The full testing sequence takes at least a day.

Newer point-of-care tests using blood or saliva (eg, particle agglutination, immunoconcentration, immunochromatography) can be done quickly (in 15 min) and simply, allowing testing in a variety of settings and immediate reporting to patients. Positive results of these rapid tests should be confirmed by standard blood tests (eg, ELISA with or without Western blot) in developed countries and repetition with one or more other rapid tests in developing countries. Negative tests need not be confirmed.

If HIV infection is suspected despite negative antibody test results (eg, during the first few weeks after infection), the plasma HIV RNA level may be measured. The nucleic acid amplification assays used are highly sensitive and specific. HIV RNA assays require advanced technology, such as reverse transcription–PCR (RT-PCR) which is sensitive to extremely low HIV RNA levels. Measuring p24 HIV antigen (p24 is a core protein of the virus) by ELISA is less sensitive and less specific than directly detecting HIV RNA in blood.

When HIV is diagnosed, CD4 count and plasma HIV RNA level should be determined; both are useful for determining prognosis and monitoring treatment. The CD4 count is calculated as the product of the following:

  • WBC count (eg, 4000 cells/mL)

  • Percentage of WBCs that are lymphocytes (eg, 30%)

  • Percentage of lymphocytes that are CD4+ (eg, 20%)

Using the numbers above, the CD4 count (4000 x 0.3 x 0.2) is 240 cells/ mL, or about 1/3 of the normal CD4 count in adults, which is about 750 ± 250/μL. Plasma HIV RNA level (viral load) reflects HIV replication rates. The higher the set point (the relatively stable virus levels that occur after primary infection), the more quickly the CD4 count decreases and the greater the risk of opportunistic infection, even in patients without symptoms.

HIV infection can be staged in order of increasing severity as category A, B, or C (AIDS— Clinical Categories of HIV Infection*). However, the capability of current treatment regimens to restore CD4 count and immune function makes these staging systems less relevant. The CD4 count after 1 to 2 yr of treatment provides an indication of ultimate immune recovery; CD4 counts may not return to the normal range despite prolonged suppression of HIV.

HIV-related conditions

Diagnosis of the various opportunistic infections, cancers, and other syndromes that occur in HIV-infected patients is discussed elsewhere in T he M anual . Many have aspects unique to HIV infection.

Hematologic disorders (eg, cytopenias, lymphomas, cancers) are common and may be usefully evaluated with bone marrow aspiration and biopsy. This procedure can also help diagnose disseminated infections with MAC, M. tuberculosis, Cryptococcus, Histoplasma, human parvovirus B19, P. jirovecii, and Leishmania. Most patients have normocellular or hypercellular marrow despite peripheral cytopenia, reflecting peripheral destruction. Iron stores are usually normal or increased, reflecting anemia of chronic disease (an iron-reutilization defect). Mild to moderate plasmacytosis, lymphoid aggregates, increased numbers of histiocytes, and dysplastic changes in hematopoietic cells are common.

HIV-associated neurologic syndromes can be differentiated via lumbar puncture with CSF analysis and contrast-enhanced CT or MRI (see Common Manifestations of HIV Infection by Organ System and elsewhere in T he M anual ).


Screening antibody tests should be offered routinely to adults and adolescents, particularly pregnant women, regardless of their perceived risk. For people at highest risk, especially sexually active people who have multiple partners and who do not practice safe sex, testing should be repeated every 6 to 12 mo. Such testing is confidential and available, often free of charge, in many public and private facilities throughout the world.


Risk of AIDS, death, or both is predicted by the

  • CD4 count in the short term

  • Plasma HIV RNA level in the longer term

For every 3-fold (0.5 log 10 ) increase in viral load, mortality over the next 2 to 3 yr increases about 50%. HIV-associated morbidity and mortality vary by the CD count, with the most deaths from HIV-related causes occurring at counts of < 50/μL. However, with effective treatment, the HIV RNA level decreases to undetectable levels, CD4 counts often increase dramatically, and risk of illness and death falls but remains higher than that for age-matched populations not infected with HIV.

Another, less well-understood prognostic factor is the level of immune activation as determined by evaluating the expression of activation markers on CD4 and CD8 lymphocytes. Activation, which may be caused by leakage of bacteria across the HIV-damaged colonic mucosa, is a strong prognostic predictor but is not used clinically because this test is not widely available and antiretroviral therapy changes the prognosis, making this test less important.

A subgroup of HIV-infected people (termed long-term nonprogressors) remains asymptomatic with high CD4 counts and low HIV levels in the blood without antiretroviral treatment. These people usually have vigorous cellular and humoral immune responses to their infecting HIV strain as measured by assays in vitro. The specificity of this effective response is shown by the following: When these people acquire a superinfection with a second strain of HIV to which their immune response is not as effective, they convert to a more typical pattern of progression. Thus, their unusually effective response to the first strain does not apply to the second strain. These cases provide a rationale for counseling HIV-infected people that they still need to avoid exposure to possible HIV superinfection through unsafe sex or needle sharing.

Cure of HIV infection has not been thought possible, and thus lifelong drug treatment is considered necessary. However, several recent cases of HIV-infected infants who were treated briefly with highly active antiretroviral therapy after diagnosis and who have remained HIV-negative for many months after stopping treatment suggests that cure is possible in this setting.


  • Combinations of antiretroviral drugs (antiretroviral therapy [ART], sometimes called highly active ART [HAART] or combined ART [cART])

  • Prophylaxis for opportunistic infections in patients at high risk

Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment is now recommended for nearly all patients. A few exceptional patients can control their HIV strain, maintaining very low blood levels of HIV and normal CD4 counts for long periods. These patients may not require ART, but studies to determine whether treating them is helpful have not been done and would be difficult because there are few of these patients and they would likely do well not taking ART for long periods.

ART aims to reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL) and restore the CD4 count to a normal level (immune restoration or reconstitution). A poor response is more likely if the CD4 count at initiation of treatment is low (especially if < 50/μL) and/or the HIV RNA level is high. However, marked improvement is likely even in patients with advanced immunosuppression. An increased CD4 count correlates with markedly decreased risk of opportunistic infections, other complications, and death. With immune restoration, patients, even those with complications that have no specific treatment (eg, HIV-induced cognitive dysfunction) or that were previously considered untreatable (eg, progressive multifocal leukoencephalopathy), may improve. Outcomes are also improved for patients with cancers (eg, lymphoma, Kaposi sarcoma) and most opportunistic infections.

ART can usually achieve its goals if patients take their drugs > 95% of the time. However, maintaining this degree of adherence is difficult. Partial suppression (failure to lower plasma levels to undetectable levels) may select for single or multiple accumulated mutations in HIV that make viruses partially or completely resistant to a single drug or entire classes of drugs. Unless subsequent treatment uses drugs of other classes to which HIV remains sensitive, treatment is more likely to fail.

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections. These reactions to successful treatment are called the immune reconstitution inflammatory syndrome (IRIS); they usually occur in the first months of treatment but are occasionally delayed. IRIS can complicate virtually any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to brief regimens of corticosteroids. Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires assessment of the persistence of active infections with cultures and can be difficult.

When to start ART in patients with acute opportunistic infections remains unclear for all but tuberculous meningitis and pneumocystis, which benefit from early ART (initiated during the management of the acute opportunistic infection). For other opportunistic infections, such as toxoplasmic encephalitis or cryptococcal meningitis, the evidence has been contradictory.

The success of ART is assessed by measuring plasma HIV RNA levels every 8 to 12 wk for the first 4 to 6 mo or until HIV levels are undetectable and every 3 to 6 mo thereafter. Increasing HIV levels are the earliest evidence of treatment failure and may precede a decreasing CD4 count by months. Maintaining patients on failing drug regimens selects for HIV mutants that are more drug-resistant. However, compared with wild-type HIV, these mutants appear less able to reduce the CD4 count, and failing drug regimens are often continued when no fully suppressive regimen can be found.

If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available drugs. Genotypic and phenotypic assays are available and can help clinicians select a new regimen that should contain at least 2 and preferably 3 drugs to which the HIV strain is more susceptible. The dominant HIV strain in the blood of patients who are taken off antiretroviral therapy may revert over months to years to the wild-type (ie, susceptible) strain because the resistant mutants replicate more slowly and are replaced by the wild type. Thus, if patients have not been treated recently, the full extent of resistance may not be apparent through resistance testing, but when treatment resumes, strains with resistance mutations often reemerge from latency and again replace the wild-type HIV strain.

Multiple classes of antiretrovirals are used in ART (see Antiretroviral Drugs). One class inhibits HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.

  • Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.

  • Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.

  • Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.

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

Antiretroviral Drugs

Generic name


Usual Adult Dose a

Some Adverse Effects b

Entry (fusion) inhibitors



90 mg sc bid

Hypersensitivity reactions, local injection site reactions, peripheral neuropathy, risk of bacterial pneumonia, insomnia, loss of appetite

Maraviroc (CCR5 inhibitor)

150–600 mg bid, depending on other drugs used

Myocardial ischemia or infarction

Integrase inhibitors


150 mg once/day

Nausea, diarrhea


400 mg bid


Non-nucleoside reverse transcriptase inhibitors

Rash (occasionally severe or life threatening), liver dysfunction



600 mg at bedtime

CNS symptoms, false-positive cannabinoid test results, excessive blood levels if the drug is taken after fatty meals


200 mg bid

Severe, potentially life-threatening rashes



200 mg once/day for 2 wk, then 200 mg bid

Severe, potentially life-threatening hepatotoxicity and rashes, especially during the first 18 wk of treatment

Increased cytochrome P-450, reducing levels of protease inhibitors, and other drugs (eg, efavirenz, clarithromycin, ethinyl estradiol, ketoconazole, itraconazole, methadone, certain antiarrhythmics, anticonvulsants, Ca channel blockers, immunosuppressants, cyclophosphamide, ergot alkaloids, fentanyl, cisapride, warfarin)


25 mg once/day

Fewer CNS adverse effects than efavirenz

Nucleoside reverse transcriptase inhibitors

Lactic acidosis (which can be life threatening), steatohepatitis



300 mg bid

Severe, potentially fatal hypersensitivity reactions with fever, rashes, nausea, vomiting, diarrhea, pharyngitis, dyspnea, and/or cough (risk is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing)

Anorexia, nausea, vomiting

Rechallenge contraindicated



400 mg once/day or 200 mg bid if 60 kg

250 mg once/day or 125 mg bid if < 60 kg

Peripheral neuropathy c , Possibly life-threatening pancreatitis d , severe hepatomegaly with steatosis, diarrhea



200 mg once/day

Minimal; skin hyperpigmentation



150 mg bid or 300 mg once/day

Peripheral neuropathy, rarely pancreatitis



40 mg bid if 60 kg

30 mg bid if < 60 kg

Peripheral neuropathy, possibly life-threatening pancreatitis (rare), hepatic steatosis, fat redistribution with lipoatrophy of face and extremities



0.75 mg tid

Peripheral neuropathy, possibly life-threatening pancreatitis d , oral ulcers



300 mg bid

Anemia and leukopenia e , rarely pancreatitis, hepatic steatosis, myopathy, myositis

Nucleotide reverse transcriptase inhibitor



300 mg once/day

Mild renal insufficiency (uncommon), other serious renal diseases (rare)

Increased levels of ddI; otherwise minimal

Protease inhibitors f

Nausea, vomiting, diarrhea, abdominal discomfort, increased serum glucose and hypercholesterolemia (common), increased abdominal fat, liver dysfunction, bleeding tendency (particularly in hemophiliacs)



1200 mg bid with food




400 mg once/day

Rash, hyperbilirubinemia


800 mg once/day, taken with ritonavir 100 mg, or 600 mg bid, taken with ritonavir 100 mg bid and with food

Severe rash, hypersensitivity, fever



1400 mg bid




800 mg tid on an empty stomach (600 mg for patients taking DLV; should not be given with ddI because concurrent use reduces levels of indinavir)

Kidney stones, occasionally obstructive (patients should ingest 1300 mL of fluid daily)

Cross-resistance with other protease inhibitors, especially ritonavir



400 mg bid (in a fixed combination with 100 mg ritonavir) with food

Altered taste, circumoral paresthesias



1250 mg bid with food



600 mg bid with food

Altered taste, circumoral paresthesias

Possibly decreased incidence and severity of adverse effects with dose reduction



1200 mg tid, within 2 h of a meal (trough levels and efficacy possibly increased when used with ritonavir)



500 mg with ritonavir 200 mg bid

Possibly life-threatening hepatitis and intracranial hemorrhage

a Doses are given orally, unless otherwise specified.

b All classes of antiretroviral drugs may contribute to chronic metabolic adverse effects, which include elevated cholesterol and triglycerides, insulin resistance, and centripetal redistribution of body fat. Adverse effects listed for drug class can occur when any drug in that class is used.

c Peripheral neuropathy may be reversible when the drug is stopped, and symptomatic treatment provides partial relief.

d If symptoms of pancreatitis (eg, nausea, vomiting, back and abdominal pain) occur, ddI or ddC must be immediately stopped until pancreatitis is confirmed or excluded.

e Anemia can be treated with transfusions or other drugs such as erythropoietin; leukopenia can be treated with colony-stimulating factor (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor).

f All are metabolized by the cytochrome P-450 system, creating potential for many drug interactions.

Combinations of 3 or 4 drugs from different classes are usually necessary to fully suppress replication of wild-type HIV. The specific drugs are chosen based on anticipated adverse effects, simplicity of regimen, concomitant conditions (eg, hepatic or renal dysfunction) and other drugs being taken (to avoid drug interactions). To maximize adherence, clinicians should choose an affordable, well-tolerated regimen that uses once/day (preferable) or bid dosing. Guidelines from expert panels for initiating, selecting, switching, and interrupting therapy and special issues concerning treatment of women and children change regularly and are updated at www.aidsinfo. .

Tablets containing fixed combinations of ≥ 3 drugs are now widely used to simplify regimens and improve adherence. Common combination tablets include

  • Stribild: Elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, plus tenofovir 300 mg, taken po once/day with food

  • Atripla: Efavirenz 600 mg, tenofovir 300 mg, plus emtricitabine 200 mg, taken po once/day on an empty stomach, preferably at bedtime

  • Complera: Rilpivirine 25 mg, emtricitabine 200 mg, plus tenofovir 300 mg, taken po once/day with food

  • Truvada: Emtricitabine 200 mg plus tenofovir 300 mg, taken once/day po with or without food

Adverse effects with combination tablets are the same as those for the individual drugs included.

Interactions between antiretrovirals may increase efficacy. For example, a subtherapeutic dose of ritonavir (100 mg once/day) can be combined with another PI (eg, lopinavir, amprenavir, indinavir, atazanavir, tipranavir). Ritonavir inhibits the hepatic enzyme that metabolizes the other PI. By slowing clearance of the therapeutically dosed PI, ritonavir increases the other drug’s levels, maintains the increased levels longer, decreases the dosing interval, and increases efficacy. Another example is lamivudine (3TC) plus zidovudine (ZDV). Use of either drug as monotherapy quickly results in resistance, but the mutation that produces resistance in response to 3TC increases the susceptibility of HIV to ZDV. Thus, when used together, they are synergistic.

Conversely, interactions between antiretrovirals may decrease the efficacy of each drug. One drug may increase elimination of another drug (eg, by inducing hepatic cytochrome P-450 enzymes responsible for elimination). Another, poorly understood effect of some NRTI combinations (eg, ZDV plus stavudine [d4T]) results in decreased antiretroviral activity without increasing drug elimination.

Combining drugs often increases the risk that either drug will have an adverse effect. Possible mechanisms include the following:

  • Hepatic metabolism of PIs by cytochrome P-450: The result is decreased metabolism (and increased levels) of other drugs.

  • Additive toxicities: For example, combining NRTIs, such as d4T and didanosine (ddI), increases the chance of adverse metabolic effects and peripheral neuropathy.

Many drugs may interfere with antiretrovirals; thus, interactions should always be checked before any new drug is started. In addition to drug interactions, grapefruit juice and St. John’s wort influence activity of some antiretroviral drugs and should be avoided. Grapefruit juice inhibits an enzyme in the GI tract that degrades the PI saquinavir and thus increases bioavailability of saquinavir. St. John's wort can enhance metabolism of PIs and NNRTIs and thus decrease plasma PI and NNRTI levels.

Adverse effects

Antiretrovirals can have serious adverse effects (see Antiretroviral Drugs). Some of these effects, notably anemia, hepatitis, renal insufficiency, pancreatitis, and glucose intolerance, can be detected by blood tests before they cause symptoms. Patients should be screened regularly, both clinically and with appropriate laboratory testing (CBC and blood tests for hyperglycemia, hyperlidemia, hepatic and pancreatic damage, and renal function), especially after new drugs are started or unexplained symptoms develop.

Metabolic effects consist of interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Subcutaneous fat is commonly redistributed from the face and extremities to the trunk, neck, breasts, and abdomen—a cosmetic effect that can stigmatize and distress patients. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial. Central obesity, hyperlipidemia, and insulin resistance, which together constitute the metabolic syndrome (see Metabolic Syndrome), increase the risk of MI, stroke, and dementia. Antivirals from all classes appear to contribute to these metabolic effects, but PIs are the most clearly involved. Some drugs, such as ritonavir or d4T commonly have metabolic effects. Others, such as tenofovir, etravirine, atazanavir or darunavir (even when combined with low-dose ritonavir), and maraviroc, appear to have small to minimal effects on lipid levels.

Mechanisms for metabolic effects appear to be multiple; one is mitochondrial toxicity. Risk of metabolic effects (highest with PIs) and mitochondrial toxicity (highest with NRTIs) varies by drug class and within drug classes (eg, among NRTIs, highest with d4T). Effects are dose-dependent and often begin in the first 1 to 2 yr of treatment. Nonalcoholic steatohepatitis and lactic acidosis are uncommon but can be lethal. Long-term effects and optimal management of metabolic effects are unclear. Lipid-lowering drugs (statins) and insulin -sensitizing drugs (glitazones) may help. (See also the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group: Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy .)

Bone complications of ART include asymptomatic osteopenia and osteoporosis, which are common. Uncommonly, osteonecrosis of large joints such as the hip and shoulder causes severe joint pain and dysfunction. Mechanisms of bone complications are poorly understood.

Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized drugs (eg, nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if drug toxicity is intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity, clinicians can safely restart most drugs as monotherapy for up to a few days. Note : The most important exception is abacavir; patients who had fever or rash during previous exposure to abacavir may develop severe, potentially fatal hypersensitivity reactions with reexposure.

Pearls & Pitfalls

  • If patients who had an adverse reaction to abacavir are reexposed to the drug, they may have a severe, potentially fatal hypersensitivity reaction, so they should not be given the drug again.

  • Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

End-of-life care

Although antiretroviral therapy has dramatically increased life expectancy for patients with AIDS, many patients still deteriorate and die. Death may result from the following:

  • Inability to take ART consistently, resulting in progressive immunosuppression

  • Occurrence of untreatable opportunistic infections and cancers

  • Liver failure due to hepatitis B or C

Death is rarely sudden; thus, patients usually have time to make plans. Nonetheless, patients should record their plans for health care early, with clear instructions for end-of-life care. Other legal documents, including powers of attorney (see Durable power of attorney for health care) and wills, should be in place. These documents are particularly important for homosexual patients because protection of assets and rights (including visitation and decision-making) for their partners may be problems.

As patients near the end of life, clinicians may need to prescribe drugs to relieve pain, anorexia, agitation, and other distressing symptoms. The profound weight loss in many people during the last stages of AIDS makes good skin care difficult. The comprehensive support provided by hospice programs helps many patients because hospice providers are unusually skilled at symptom management, and they support caregivers and patient autonomy.


Vaccines against HIV have been difficult to develop because HIV surface proteins mutate easily, resulting in an enormous diversity of antigenic types. Nonetheless, various vaccine candidates are under study, and a few have shown promise in clinical trials. At the present time, there is no effective AIDS vaccine.

Prevention of transmission

Vaginal microbicides (including antiretroviral drugs) inserted before sexual contact have thus far proved ineffective, and some appear to increase risk for women, perhaps by damaging natural barriers to HIV.

Effective measures include the following:

  • Public education: Education is effective and appears to have decreased rates of infection in some countries, notably Thailand and Uganda. Because sexual contact accounts for most cases, teaching people to avoid unsafe sex practices is the most relevant measure (see HIV Transmission Risk for Several Sexual Activities).

  • Safe sex practices: Unless both partners are known to be free of HIV and remain monogamous, safe sex practices are essential. Safe sex practices are also advised when both partners are HIV-positive; unprotected sex between HIV-infected people may expose a person to resistant or more virulent strains of HIV and to other viruses (eg, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, hepatitis B virus) that cause severe disease in AIDS patients. Condoms offer the best protection. Oil-based lubricants should not be used because they may dissolve latex, increasing the risk of condom failure. (See also the recommendations of the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America: Incorporating HIV Prevention into the Medical Care of Persons Living with HIV .)

  • Counseling for parenteral drug users: Counseling about the risk of sharing needles is important but is probably more effective if combined with provision of sterile needles, treatment of drug dependence, and rehabilitation.

  • Confidential testing for HIV infection: Testing should be offered routinely to adolescents and adults in virtually all health care settings. To facilitate routine testing, some states no longer require written consent or extensive pre-test counseling.

  • Counseling for pregnant women: Mother-to-child transmission has been virtually eliminated by HIV testing, treatment with ART, and, in developed countries, use of breast milk substitutes. If pregnant women test positive for HIV, risk of maternal-fetal transmission should be explained (see Prevention of perinatal transmission). Pregnant women who do not accept immediate treatment for their HIV infection should be given therapy to protect the unborn baby, typically beginning at about 14 wk gestation. Combination therapy is typically used because it is more effective than monotherapy and less likely to result in drug resistance. Some drugs can be toxic to the fetus or woman and should be avoided. If women meet criteria for ART, they should begin a regimen tailored to their history and stage of pregnancy and continue it throughout pregnancy. Cesarean delivery can also reduce risk of transmission. Some women choose to terminate their pregnancy because HIV can be transmitted in utero to the fetus or for other reasons.

  • Screening of blood and organs: Transmission by blood transfusion is still remotely possible in the US because antibody results may be false-negative during early infection. Currently, screening blood for antibody and p24 antigen is mandated in the US and probably further reduces risk of transmission. Risk is reduced further by asking people with risk factors for HIV infection, even those with recent negative HIV antibody test results, not to donate blood or organs for transplantation. However, use of sensitive HIV screening tests and deferral of donors of organs, blood, and blood products has not been implemented consistently in developing countries.

  • Preexposure prophylaxis with antiretrovirals (PrEP): In PrEP, people who are not infected with HIV but are at high risk (eg, by having an HIV-infected sexual partner) take an antiretroviral drug daily to reduce their risk of infection. The combination of tenofovir plus emtricitabine (TDF/FTC) can be used. Use of PrEP does not eliminate the need to use other methods of reducing risk of HIV infection, including using condoms and avoiding high-risk behaviors (eg, needle sharing). Data concerning infants of HIV-negative mothers taking TDF/FTC PrEP during pregnancy are incomplete, but currently, no adverse effects have been reported in children born to HIV-infected women treated with TDF/FTC. Use of PrEP to reduce the risk of HIV infection in injection drug users is being studied. For the current CDC recommendations, see Pre-Exposure Prophylaxis (PrEP) .

  • Circumcision of men: In young African men, circumcision has been shown to reduce their risk of acquiring HIV infection from female partners during vaginal sex by about 50%; male circumcision is probably similarly effective elsewhere. Whether male circumcision reduces HIV transmission from HIV-positive men to women or reduces the risk of acquiring HIV from an infected male partner is unknown.

  • Universal precautions: Medical and dental health care practitioners should wear gloves in situations that may involve contact with any patient’s mucous membranes or body fluids and should be taught how to avoid needlestick accidents. Home caregivers of patients with HIV infection should wear gloves if their hands may be exposed to body fluids. Surfaces or instruments contaminated by blood or other body fluids should be cleaned and disinfected. Effective disinfectants include heat, peroxide, alcohols, phenolics, and hypochlorite (bleach). Isolation of HIV-infected patients is unnecessary unless indicated by an opportunistic infection (eg, TB). Guidelines to prevent transmission from infected practitioners to patients have not been established. See also the CDC's Recommendations for Preventing Transmission of Human Immunodeficiency Virus and Hepatitis B Virus to Patients During Exposure-Prone Invasive Procedures .

  • Treatment of HIV infection: Treatment with ART lowers the risk of transmission

Postexposure prophylaxis (PEP)

Potential consequences of exposure to HIV have prompted the development of policies and procedures, particularly preventive treatment, to decrease risk of infection to health care workers. Preventive treatment is indicated after penetrating injuries involving HIV-infected blood (usually needlesticks) or heavy exposure of mucous membranes (eye or mouth) to infected body fluids such as semen, vaginal fluids, or other body fluids containing blood (eg, amniotic fluid) . Risk of infection due to exposure to body fluids such as saliva, urine, or sweat is very low.

After initial exposure to blood, the exposed area is immediately cleaned with soap and water for skin exposures and with antiseptic for puncture wounds. If mucous membranes are exposed, the area is flushed with large amounts of water.

The following are documented:

  • Type of exposure and time elapsed since exposure

  • Clinical information (including risk factors and serologic tests for HIV) about the source patient for the exposure and the person exposed

Type of exposure is defined by

  • Which body fluid was involved

  • Whether exposure involved a penetrating injury (eg, needlestick, cut with sharp object) and how deep the injury was

  • Whether the fluid had contact with nonintact skin (eg, abraded or chapped skin) or mucous membrane

Risk of infection is categorized as high or low:

  • High: Involves a deep wound made by a hollow-bore needle with visible blood on it, direct exposure to a needle from a vein or an artery of the source patient, or mucocutaneous exposure with a large amount of blood from a high-risk source (viral load > 1500 copies/mL)

  • Low: Involves a solid needle, superficial injury, or a low-risk source (viral load < 1500 copies/mL) and includes most mucocutaneous exposures

Risk of infection is about 0.3% (1:300) after a typical percutaneous exposure and about 0.09% (1:1100) after mucous membrane exposure, but these risks vary, reflecting the amount of HIV transferred to the person with the injury.

The source is qualified by whether it is known or unknown. If the source is unknown (eg, a needle on the street or in a sharps disposal container), risk should be assessed based on the circumstances of the exposure (eg, whether the exposure occurred in an area where injection drug use is prevalent, whether a needle discarded in a drug-treatment facility was used). If the source is known but HIV status is not, the source is assessed for HIV risk factors, and prophylaxis is considered (see Postexposure Prophylaxis Recommendations).

Postexposure Prophylaxis Recommendations

Infection Status of Source


HIV-positive, class 1 (asymptomatic HIV infection or known low viral load [< 1500 RNA copies/mL])

2-drug PEP for less severe exposure*

3-drug PEP for more severe exposure

HIV-positive, class 2 (symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load)

3-drug PEP

Unknown HIV status of source or unknown source

Generally, no PEP warranted ; however, consideration of 2-drug PEP if source has HIV risk factors or if setting is likely to involve exposure to HIV-infected people

HIV-negative (based on antibody tests or nucleic acid amplification assays)

No PEP warranted

*Less severe exposure may involve a solid needle or superficial injuries.

More severe exposure may involve a hollow-bore needle, deep puncture, visible blood on the device, or a needle used in a patient’s artery or vein.

PEP is optional and should be based on an individualized decision by the exposed person and the treating clinician. If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be stopped.

PEP = postexposure prophylaxis.

Adapted from Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. Morbidity and Mortality Weekly Report 54 (RR09):1–17, September 30, 2005 available at

The goal is to start PEP as soon after exposure as possible if prophylaxis is warranted. CDC recommends providing PEP within 24 to 36 h after exposure; a longer interval after exposure requires the advice of an expert.

Use of PEP is determined by risk of infection; guidelines recommend antiretroviral therapy with 2 NRTIs (eg, ZDV plus 3TC) for low risk and the addition of one or more drugs (eg, 2 NRTIs plus a PI or an NNRTI) for high risk; drugs are given for 28 days. Nevirapine is avoided because of the rare possibility of severe hepatitis. Although evidence is not conclusive, ZDV alone probably reduces risk of transmission after needlestick injuries by about 80%. For detailed recommendations, see the CDC's Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis or the University of California, San Francisco's Post-Exposure Prophylaxis (PEP) .

If the source’s virus is known or suspected to be resistant to 1 drug, an expert in antiretroviral therapy and HIV transmission should be consulted. However, clinicians should not delay PEP pending expert consultation or drug susceptibility testing. Also, clinicians should provide immediate evaluation and face-to-face counseling and not delay follow-up care.

Prevention of opportunistic infections

(See also the US Public Health Service and the HIV Medicine Association of the Infectious Diseases Society of America’s Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents .)

Effective chemoprophylaxis is available for many opportunistic infections and reduces rates of disease due to P. jirovecii, Candida, Cryptococcus, and MAC. If therapy restores CD4 counts to above threshold values for > 3 mo, chemoprophylaxis can be stopped.

Primary prophylaxis depends on CD count:

  • CD4 count < 200/μL or oropharyngeal candidiasis: Prophylaxis against P. jirovecii pneumonia is recommended. Double-strength trimethoprim/sulfamethoxazole (TMP/SMX) tablets given once/day or 3 times/wk are effective for both infections. Some adverse effects can be minimized with the 3 times/wk dose or by gradual dose escalation. Some patients who cannot tolerate TMP/SMX can tolerate dapsone (100 mg once/day). For the few patients who cannot tolerate either drug because of a troublesome adverse effect (eg, fever, neutropenia, rash), aerosolized pentamidine 300 mg once/day or atovaquone 1500 mg once/day can be used.

  • CD4 count < 50/μL: Prophylaxis against disseminated MAC consists of azithromycin or clarithromycin; if neither of these drugs is tolerated, rifabutin can be used. Azithromycin can be given weekly as two 600-mg tablets; it provides protection (70%) similar to daily clarithromycin and does not interact with other drugs.

If latent TB is suspected (based on tuberculin skin tests, interferon-gamma release assays, high-risk exposure, personal history of active TB, or residence in a region with high TB prevalence), regardless of CD4 count, patients should be given isoniazid 5 mg/kg (up to 300 mg) po once/day plus pyridoxine (vitamin B 6 ) 10 to 25 mg po once/day for 9 mo to prevent reactivation.

For primary prophylaxis against some fungal infections (eg, esophageal candidiasis, cryptococcal meningitis or pneumonia), oral fluconazole 100 to 200 mg once/day or 400 mg weekly is successful but is infrequently used because the cost per infection prevented is high and diagnosis and treatment of these infections are usually successful.

Secondary prophylaxis (after control of the initial infection) is indicated if patients have had the following:

  • Recurrent oral, vaginal, or esophageal candidiasis or cryptococcal infections: Fluconazole is used.

  • Histoplasmosis: Itraconazole is used (see Treatment).

  • Latent toxoplasmosis: This asymptomatic condition is indicated by serum antibodies (IgG) to Toxoplasma gondii. TMP/SMX (in doses used to prevent P. jirovecii pneumonia) is used to prevent reactivation and consequent toxoplasmic encephalitis. Latent infection is less common (about 15% of adults) in the US than in Europe and most developing countries (up to 70 to 80% of adults).

  • P. jirovecii pneumonia (see Pneumocystis jirovecii Pneumonia)

  • Herpes simplex infection (see Herpes Simplex Virus (HSV) Infections)

  • Aspergillosis (possibly—see Aspergillosis)

Detailed guidelines for prophylaxis of fungal (including Pneumocystis), viral, mycobacterial, and toxoplasmic infections are available at .


Immunizations (using nonviable vaccines) is indicated for pneumococcal disease (23-valent vaccine if the CD4 count is > 200/μL), influenza A (all patients annually), and hepatitis B and A (for patients at risk); these vaccines are effective less often in patients who are HIV-positive than in those who are HIV-negative. Vaccines against human papillomavirus (for prevention of HPV-related cervical and anal cancers) and herpes zoster virus (for boosting immunity to prevent reactivation as zoster) could be useful in HIV-infected adults. The safety and efficacy of both vaccines in HIV-infected adults and children are under study. Because live-virus vaccines are potentially dangerous for patients with severe immunosuppression, expert opinion should be sought when dealing with patients at risk of primary varicella; recommendations vary (see Vaccination and Considerations for Use of Live Vaccines in Children With HIV Infection).

Key Points

  • HIV infects CD4+ lymphocytes and thus interferes with cell-mediated and, to a lesser extent, humoral immunity.

  • HIV is spread mainly by sexual contact, parenteral exposure to contaminated blood, and prenatal and perinatal maternal transmission.

  • Frequent viral mutations combined with immune system damage significantly impair the body's ability to clear the HIV infection.

  • Various opportunistic infections and cancers can develop and are the usual cause of death in untreated patients.

  • Diagnose using antibody tests, and monitor by measuring viral load and CD4 count.

  • Treat with a combinations of antiretroviral drugs, which can restore immune function to nearly normal in most patients if they take the drugs consistently.

  • Use postexposure and preexposure antiretroviral prophylaxis when indicated.

  • Give primary prophylaxis against opportunistic infections based on the CD4 count.

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