(See also Human Immunodeficiency Virus (HIV) Infection in Infants and Children, the National Institute's of Health AIDSInfo web site 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.)

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. 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 or antigen testing. Screening should be routinely offered to all adults and adolescents. Treatment aims to suppress HIV replication by using combinations of drugs that inhibit HIV enzymes.

(See also 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 Sidebar 1: Human Immunodeficiency Virus (HIV): HTLV Infections), cause disorders in people.

Sidebar 1
HTLV Infections
Infection with human T-lymphotropic virus (HTLV) 1 or 2 can cause T-cell leukemias and lymphomas, lymphadenopathy, hepatosplenomegaly, skin lesions, and immunocompromise. Some immunocompromised patients develop infections similar to those that occur in patients with AIDS. HTLV-1 can also cause myelopathy (see Spinal Cord Disorders: Tropical Spastic Paraparesis/HTLV-1–Associated Myelopathy (TSP/HAM)). Most cases are transmitted from mother to child by breastfeeding, but HTLV-1 can be transmitted sexually and through blood.

AIDS is defined as HIV infection that leads to any of the disorders in clinical category B or C of HIV infection (see Table 1: Human Immunodeficiency Virus (HIV): Clinical Categories of HIV Infection*) or a CD4+ T lymphocyte (helper cell—see Biology of the Immune System: T cells) count of < 200/μL. The disorders in categories B and C are

• Serious opportunistic infections
• Certain cancers, such as Kaposi's sarcoma and non-Hodgkin lymphoma, to which defective cell-mediated immunity predisposes
• Neurologic dysfunction

Table 1
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Clinical Categories of HIV Infection* Category Disorder or Symptoms A Asymptomatic Persistent generalized adenopathy Symptoms of acute primary HIV infection B 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 Listeriosis Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess Peripheral neuropathy C 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's sarcoma Lymphoma, Burkitt's 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 disease progression, they predict prognosis less well in patients receiving current treatments. †Added in the 1993 expansion of the AIDS surveillance case definition.

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 less virulent than HIV-1.

HIV-1 originated in rural 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. More than 40 million people are infected worldwide. Of the 3 million annual deaths and 11,000 new daily infections, 95% occur in the developing world, 1/2 are in women, and 1/7 are in children < 15 yr.

Transmission

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 virions or infected cells. Transmission is more likely with higher levels of virions, as is typical during primary infection, even when people 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 generally by

• Direct transfer of bodily fluids through sexual intercourse
• Sharing of blood-contaminated needles
• Childbirth
• Breastfeeding
• Medical procedures (eg, transfusions, exposure to contaminated instruments)

Sexual practices such as fellatio and cunnilingus appear to be relatively low risk but not absolutely safe (see Table 2: Human Immunodeficiency Virus (HIV): HIV Transmission Risk of 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, chlamydia, trichomoniasis, especially those that cause ulceration (eg, chancroid, herpes, syphilis), increase risk. 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 fluid are higher, in younger people, and in people with ulcerative genital diseases.

Table 2
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HIV Transmission Risk of Several Sexual Activities Risk Activity 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 Low 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 High Vaginal or anal intercourse with or without ejaculation if a condom is not used or is not used correctly

HIV can be transmitted from mother to offspring transplacentally or perinatally; without treatment, risk of transmission is about 25 to 35%. HIV is also excreted in breast milk, and breastfeeding by HIV-infected mothers may transmit HIV to about 75% of infants who had previously escaped infection. Because many women of childbearing age are infected, incidence of AIDS in children has increased (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children).

Risk of transmission after skin penetration with a medical instrument contaminated with infected blood is on average about 1/300 without treatment. Immediate antiretroviral treatment 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 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.

Although screening of blood donors has minimized risk of transmission via transfusion, a small risk still exists because antibody-based screening tests may miss early infections (see Human Immunodeficiency Virus (HIV): Prevention). Current risk of transmitting HIV via blood transfusion is probably between 1/500,000 and 1/1,000,000 per unit transfused.

Epidemiology

HIV has spread in 2 epidemiologically distinct patterns:

• Male homosexual intercourse or contact with infected blood (eg, through sharing needles in IV drug users; before effective screening of donors, through transfusions)
• Heterosexual intercourse (affecting men and women equally)

The first pattern usually predominates in developed countries; the second pattern predominates in Africa, South America, and southern Asia. In some countries (eg, Brazil, Thailand), both patterns are common. 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, a deficient system of medical care, and lack of effective drugs.

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 toxoplasmosis and TB is high in the general population, and thus enormous increases in active TB have followed the HIV epidemic 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. In the US and Europe, human herpesvirus 8 infection, which causes Kaposi's sarcoma, is common among homosexual and bisexual men but uncommon among other HIV patients. Thus, in the US, > 90% of AIDS patients who develop Kaposi's sarcoma are homosexual or bisexual men.

Pathophysiology

HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see Fig. 1: Human Immunodeficiency Virus (HIV): Simplified HIV life cycle.). After attachment, HIV RNA and 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 HIV integrase. With each cell division, the integrated proviral DNA is duplicated along with the host DNA. Proviral HIV DNA is transcribed to viral RNA and translated to HIV proteins, including the envelope glycoproteins 40 and 120. The HIV proteins are assembled into HIV virions at the inner cell membrane and budded from the cell surface; 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 form.

Fig. 1
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 virus.

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 10⁸ to 10⁹ 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

The main consequence of HIV infection is damage to the immune system, specifically loss of CD4+ lymphocytes, which are involved in cell-mediated and, to a lesser extent, humoral immunity. CD4+ lymphocyte 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 (> 10⁶ 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, a variety of opportunistic pathogens may produce clinical disease, often by reactivating from latent states.

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

Other tissues

HIV also infects nonlymphoid monocytic cells (eg, dendritic cells in the skin, macrophages, brain microglia) and cells of the 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. Thus, HIV levels and resistance patterns in these compartments may differ from those in plasma.

Disease progression

Antibodies to HIV are measurable usually 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 antibodies are generated.

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

• CD4 count
• Exposure to potentially opportunistic pathogens

Plasma HIV virion levels, expressed as HIV RNA copies/mL, stabilize after about 6 mo at values (set points) that vary widely among patients but average 30,000 to 100,000/mL (4.2 to 5 log₁₀/mL). The higher the 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 of specific opportunistic infections increases below threshold CD4 counts of about 200/μL for some 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; CMV and Mycobacterium avium complex (MAC) infections are a risk when the CD4 count is < 50/μL. For every 3-fold (0.5 log₁₀) 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.

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; it is characterized by fever, malaise, rash, arthralgia, generalized lymphadenopathy, and sometimes aseptic meningitis. Symptoms are often mistaken for infectious mononucleosis or benign, nonspecific viral syndromes.

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 may result from HIV directly or from opportunistic infections. The following are most common:

• Lymphadenopathy
• White plaques due to oral candidiasis
• Painful rash due to herpes zoster
• Diarrhea
• Fatigue
• Fever with intermittent sweats

Asymptomatic, mild-to-moderate cytopenias (eg, leukopenia, anemia, thrombocytopenia) are also common. In some patients, progressive wasting occurs.

Eventually, 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 Table 1: Human Immunodeficiency Virus (HIV): 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 sepsis. In patients with HIV infection, certain syndromes are common and may require different considerations (see Table 3: Human Immunodeficiency Virus (HIV): Common Manifestations of HIV Infection by Organ System). Some patients present with cancers (eg, Kaposi's sarcoma, B-cell lymphomas) that occur more frequently, are unusually severe, or have unique features in patients with HIV infection (see Human Immunodeficiency Virus (HIV): Cancers Common in HIV-Infected Patients). In other patients, neurologic dysfunction may occur.

Table 3
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Common Manifestations of HIV Infection by Organ System Syndrome Cause Diagnostic Evaluation Treatment Symptoms/Comments Neurologic Mild to severe dementia 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 Does not always progress to AIDS dementia 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 due to CMV polyradiculopathy Acute or subacute focal encephalitis (see Brain Infections: Encephalitis) Toxoplasma gondii CT or MRI to check for ring-enhancing lesions, especially near basal ganglia Antibody testing of CSF (sensitive but not specific) Response to empiric antiviral treatment Brain biopsy (rarely indicated) Pyrimethamine, folinic acid, sulfadiazine, and possibly trimethoprim/sulfamethoxazole (clindamycin if allergic to sulfa—see Extraintestinal Protozoa: Treatment) Prophylaxis with clindamycin and pyrimethamine or trimethoprim/ sulfamethoxazole (as for Pneumocystis pneumonia) indicated for patients with a CD4 count of < 200/μL and previous toxoplasmosis or positive antibodies Subacute encephalitis CMV (see Herpesviruses: Cytomegalovirus (CMV) Infection) Less often, herpes simplex virus or varicella-zoster virus CSF PCR 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 Spinal Cord Disorders: Acute Transverse Myelitis) CMV Spinal cord MRI CSF PCR Antiviral drugs (see Viruses: Antiviral drugs) Simulates Guillain-Barré syndrome Progressive encephalitis of white matter only Progressive multifocal leukoencephalopathy (see Brain Infections: Progressive Multifocal Leukoencephalopathy (PML)) or HIV Brain MRI CSF testing Antiretroviral drugs Usually fatal within a few months May respond to antiretroviral drugs Subacute meningitis Cryptococcus, Histoplasma, or Mycobacterium tuberculosis CT or MRI CSF stains and cultures Treatment of cause Good outcomes if patients are treated early Peripheral neuropathy (see Peripheral Nervous System and Motor Unit Disorders: Peripheral Neuropathy) Direct effects of HIV or CMV or antiviral toxicity History Sensory and motor testing Treatment of cause or withdrawal of toxic drugs Very common Not quickly reversible Ophthalmologic Retinitis CMV Direct retinoscopy Specific anti-CMV drugs (see Herpesviruses: Treatment) Requires examination by specialist Cardiac Cardiomyopathy Direct viral damage to cardiac myocytes Echocardiography Antiretroviral drugs Symptoms of heart failure Renal 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 Oral candidiasis (see Fungi: Candidiasis (Invasive)) Immunosuppression by HIV Examination Systemic antifungals (see Fungi: Antifungal Drugs) Possibly painless in early stages Intraoral ulcers Herpes simplex virus or aphthous stomatitis see Symptoms of Dental and Oral Disorders: Evaluation see Symptoms of Dental and Oral Disorders: Treatment May be severe and result in undernutrition Periodontal disease Mixed oral bacterial flora Examination Improved hygiene and nutrition Antibiotics May be severe, with bleeding, swelling, and tooth loss Painless intraoral mass Kaposi's sarcoma or lymphoma Biopsy Treatment of cause — Painless white filiform patches on the sides of the tongue (oral hairy leukoplakia) Epstein-Barr virus Examination Acyclovir Usually asymptomatic GI Esophagitis 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 or Cryptosporidium 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 Examination Gram staining and culture Biopsy Treatment of cause High incidence in homosexual men Hepatocellular damage due to hepatitis viruses, opportunistic infections, or antiviral toxicity TB, MAC, CMV, or peliosis (bartonellosis) Chronic hepatitis B or C, 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) Skin Herpes zoster Varicella-zoster virus Clinical evaluation (see Herpesviruses: Diagnosis) Acyclovir or related drugs Common Possible prodrome of mild to severe pain or tingling before skin lesions Herpes simplex ulcers Herpes simplex virus Usually clinical evaluation (see Herpesviruses: Diagnosis) Antiviral drugs if lesions are severe, extensive, persistent, or disseminated Atypical lesions of herpes simplex that are extensive, severe, or persistent Scabies Sarcoptes scabiei See Parasitic Skin Infections: Diagnosis See Parasitic Skin Infections: Treatment Possibly severe hyperkeratotic lesions Violaceous or red papules or nodules Kaposi's sarcoma or bartonellosis Biopsy Treatment of cause — Centrally umbilicated skin lesions Cryptococcosis or molluscum contagiosum see Viral Skin Diseases: Diagnosis; see Fungi: Diagnosis see Viral Skin Diseases: Treatment; see Fungi: Treatment May be the presenting sign of cryptococcemia Pulmonary 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 sometimes necessary Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Mild hypoxia or increased alveolar-arterial O2 gradient possibly occurring before evidence of pneumonia on x-ray Acute (occasionally subacute) pneumonia Typical bacterial pathogens or Haemophilus, Pseudomonas, Nocardia, or Rhodococcus See Pneumonia 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 Tracheobronchitis Candida or herpes simplex virus — Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Subacute or chronic pneumonia or mediastinal adenopathy Kaposi's sarcoma or B-cell lymphoma Chest CT Bronchoscopy Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Systemic Systemic septicemia due to disseminated opportunistic infections M. tuberculosis, MAC, or H. capsulatum Blood cultures Bone marrow examination Treatment of cause — Gynecologic Vaginal candidiasis Candida See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Candidal Vaginitis See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Treatment Possibly increased in severity or recurrent Pelvic inflammatory disease Neisseria gonorrhoeae, Chlamydia trachomatis, or other usual pathogens (see Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Pelvic Inflammatory Disease (PID)) See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Diagnosis See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Treatment Possibly increased in severity, atypical, and difficult to treat Hematologic Anemia Multifactorial: HIV-induced bone marrow suppression Immune-mediated peripheral destruction Anemia of chronic disease Infections, particularly human parvovirus B-19, disseminated MAC, or histoplasmosis Cancers See Approach to the Patient With Anemia: Evaluation of Anemia For parvovirus, bone marrow examination (to check for multinucleated erythroblasts) or serum 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 Thrombocytopenia Immune thrombocytopenia (see Thrombocytopenia and Platelet Dysfunction: 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's 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 Neutropenia HIV-induced bone marrow suppression, immune-mediated peripheral destruction, infections, cancer, or drug toxicity See Neutropenia and Lymphocytopenia: Diagnosis For severe neutropenia (< 500/μL) plus fever, immediate broad-spectrum antibiotics (see Neutropenia and Lymphocytopenia: Treatment). If drug-induced, granulocyte or granulocyte-macrophage colony-stimulating factors — CMV = cytomegalovirus; IVIG = IV immune globulin; MAC = Mycobacterium avium complex. Common Manifestations of HIV Infection by Organ System Syndrome Cause Diagnostic Evaluation Treatment Symptoms/Comments Neurologic Mild to severe dementia 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 Does not always progress to AIDS dementia 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 due to CMV polyradiculopathy Acute or subacute focal encephalitis (see Brain Infections: Encephalitis) Toxoplasma gondii CT or MRI to check for ring-enhancing lesions, especially near basal ganglia Antibody testing of CSF (sensitive but not specific) Response to empiric antiviral treatment Brain biopsy (rarely indicated) Pyrimethamine, folinic acid, sulfadiazine, and possibly trimethoprim/sulfamethoxazole (clindamycin if allergic to sulfa—see Extraintestinal Protozoa: Treatment) Prophylaxis with clindamycin and pyrimethamine or trimethoprim/ sulfamethoxazole (as for Pneumocystis pneumonia) indicated for patients with a CD4 count of < 200/μL and previous toxoplasmosis or positive antibodies Subacute encephalitis CMV (see Herpesviruses: Cytomegalovirus (CMV) Infection) Less often, herpes simplex virus or varicella-zoster virus CSF PCR 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 Spinal Cord Disorders: Acute Transverse Myelitis) CMV Spinal cord MRI CSF PCR Antiviral drugs (see Viruses: Antiviral drugs) Simulates Guillain-Barré syndrome Progressive encephalitis of white matter only Progressive multifocal leukoencephalopathy (see Brain Infections: Progressive Multifocal Leukoencephalopathy (PML)) or HIV Brain MRI CSF testing Antiretroviral drugs Usually fatal within a few months May respond to antiretroviral drugs Subacute meningitis Cryptococcus, Histoplasma, or Mycobacterium tuberculosis CT or MRI CSF stains and cultures Treatment of cause Good outcomes if patients are treated early Peripheral neuropathy (see Peripheral Nervous System and Motor Unit Disorders: Peripheral Neuropathy) Direct effects of HIV or CMV or antiviral toxicity History Sensory and motor testing Treatment of cause or withdrawal of toxic drugs Very common Not quickly reversible Ophthalmologic Retinitis CMV Direct retinoscopy Specific anti-CMV drugs (see Herpesviruses: Treatment) Requires examination by specialist Cardiac Cardiomyopathy Direct viral damage to cardiac myocytes Echocardiography Antiretroviral drugs Symptoms of heart failure Renal 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 Oral candidiasis (see Fungi: Candidiasis (Invasive)) Immunosuppression by HIV Examination Systemic antifungals (see Fungi: Antifungal Drugs) Possibly painless in early stages Intraoral ulcers Herpes simplex virus or aphthous stomatitis see Symptoms of Dental and Oral Disorders: Evaluation see Symptoms of Dental and Oral Disorders: Treatment May be severe and result in undernutrition Periodontal disease Mixed oral bacterial flora Examination Improved hygiene and nutrition Antibiotics May be severe, with bleeding, swelling, and tooth loss Painless intraoral mass Kaposi's sarcoma or lymphoma Biopsy Treatment of cause — Painless white filiform patches on the sides of the tongue (oral hairy leukoplakia) Epstein-Barr virus Examination Acyclovir Usually asymptomatic GI Esophagitis 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 or Cryptosporidium 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 Examination Gram staining and culture Biopsy Treatment of cause High incidence in homosexual men Hepatocellular damage due to hepatitis viruses, opportunistic infections, or antiviral toxicity TB, MAC, CMV, or peliosis (bartonellosis) Chronic hepatitis B or C, 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) Skin Herpes zoster Varicella-zoster virus Clinical evaluation (see Herpesviruses: Diagnosis) Acyclovir or related drugs Common Possible prodrome of mild to severe pain or tingling before skin lesions Herpes simplex ulcers Herpes simplex virus Usually clinical evaluation (see Herpesviruses: Diagnosis) Antiviral drugs if lesions are severe, extensive, persistent, or disseminated Atypical lesions of herpes simplex that are extensive, severe, or persistent Scabies Sarcoptes scabiei See Parasitic Skin Infections: Diagnosis See Parasitic Skin Infections: Treatment Possibly severe hyperkeratotic lesions Violaceous or red papules or nodules Kaposi's sarcoma or bartonellosis Biopsy Treatment of cause — Centrally umbilicated skin lesions Cryptococcosis or molluscum contagiosum see Viral Skin Diseases: Diagnosis; see Fungi: Diagnosis see Viral Skin Diseases: Treatment; see Fungi: Treatment May be the presenting sign of cryptococcemia Pulmonary 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 sometimes necessary Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Mild hypoxia or increased alveolar-arterial O2 gradient possibly occurring before evidence of pneumonia on x-ray Acute (occasionally subacute) pneumonia Typical bacterial pathogens or Haemophilus, Pseudomonas, Nocardia, or Rhodococcus See Pneumonia 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 Tracheobronchitis Candida or herpes simplex virus — Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Subacute or chronic pneumonia or mediastinal adenopathy Kaposi's sarcoma or B-cell lymphoma Chest CT Bronchoscopy Treatment of cause Possibly cough, tachypnea, and chest discomfort at presentation Systemic Systemic septicemia due to disseminated opportunistic infections M. tuberculosis, MAC, or H. capsulatum Blood cultures Bone marrow examination Treatment of cause — Gynecologic Vaginal candidiasis Candida See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Candidal Vaginitis See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Treatment Possibly increased in severity or recurrent Pelvic inflammatory disease Neisseria gonorrhoeae, Chlamydia trachomatis, or other usual pathogens (see Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Pelvic Inflammatory Disease (PID)) See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Diagnosis See Vaginitis, Cervicitis, and Pelvic Inflammatory Disease (PID): Treatment Possibly increased in severity, atypical, and difficult to treat Hematologic Anemia Multifactorial: HIV-induced bone marrow suppression Immune-mediated peripheral destruction Anemia of chronic disease Infections, particularly human parvovirus B-19, disseminated MAC, or histoplasmosis Cancers See Approach to the Patient With Anemia: Evaluation of Anemia For parvovirus, bone marrow examination (to check for multinucleated erythroblasts) or serum 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 Thrombocytopenia Immune thrombocytopenia (see Thrombocytopenia and Platelet Dysfunction: 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's 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 Neutropenia HIV-induced bone marrow suppression, immune-mediated peripheral destruction, infections, cancer, or drug toxicity See Neutropenia and Lymphocytopenia: Diagnosis For severe neutropenia (< 500/μL) plus fever, immediate broad-spectrum antibiotics (see Neutropenia and Lymphocytopenia: Treatment). If drug-induced, granulocyte or granulocyte-macrophage colony-stimulating factors — CMV = cytomegalovirus; IVIG = IV immune globulin; MAC = Mycobacterium avium complex.

Diagnosis

• 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 Table 1: Human Immunodeficiency Virus (HIV): 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 time.

Newer point-of-care tests using blood or saliva (eg, particle agglutination, immunoconcentration, immunochromatography) can be done quickly and simply, allowing testing in a variety of settings and immediate reporting to patients. Positive results of these tests should be confirmed by standard blood tests (eg, Western blot).

If HIV infection is suspected despite negative antibody test results (eg, during the first few weeks), plasma may be tested for HIV RNA (virion). The nucleic acid amplification assays used are highly sensitive and specific. HIV RNA assays require advanced technology, such as reverse transcription–PCR (RT-PCR) or branched DNA (bDNA) measurement, which are sensitive to extremely low HIV RNA levels. Measurement of p24 HIV antigen by ELISA is a less sensitive and less specific alternative for directly detecting HIV protein 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
• Percentage of WBCs that are lymphocytes
• Percentage of lymphocytes that are CD4+

Normally, the CD4 count in adults 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 (see Table 1: Human Immunodeficiency Virus (HIV): Clinical Categories of HIV Infection*). Staging is by clinical manifestations or the CD4 count (A: ≥ 500; B: 200 to 499; and C: < 200/μL). The clinical category is determined by the most severe manifestation patients have had, past or present. Patients are never restaged to a less severe category.

HIV-related conditions

Diagnosis of the various opportunistic infections, cancers, and other syndromes that occur in HIV-infected patients is discussed elsewhere in The Manual. Many have aspects unique to HIV infection (see Table 1: Human Immunodeficiency Virus (HIV): Clinical Categories of HIV Infection* and see Human Immunodeficiency Virus (HIV): Cancers Common in HIV-Infected Patients).

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 Table 3: Human Immunodeficiency Virus (HIV): Common Manifestations of HIV Infection by Organ System and elsewhere in The Manual).

Screening

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.

Prognosis

Risk of AIDS, death, or both is predicted by the CD4 count in the short term and by plasma HIV RNA level in the longer term. For every 3-fold (0.5 log₁₀) 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.

A subgroup of HIV-infected persons (termed long-term nonprogressors) remains asymptomatic with high CD4 counts and low HIV levels in the blood without antiretroviral treatment. They 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 examples of superinfection with a second strain of HIV to which their immune response is not as effective, resulting in their conversion to a more typical pattern of progression. Thus, their unusually effective response to the first strain did not apply to the second strain. These cases provide a rationale for counseling HIV-infected people not to expose themselves to possible HIV superinfection through unsafe sex or needle sharing.

Treatment

• Combinations of antiretroviral drugs
• Sometimes prophylaxis for opportunistic infections

Because adequate antiretroviral therapy can cause significant long-term morbidity, it is not recommended for everyone. Current indications include a CD4 count of < 350/μL and an HIV RNA level of > 55,000 copies/mL. Use of potent combinations of antiretroviral drugs for HIV therapy (highly active antiretroviral therapy [HAART]) aims to reduce the plasma HIV RNA level and restore the CD4 count (immune restoration or reconstitution). The lower the pretreatment CD4 count and the higher the HIV RNA level, the less likely treatment is to succeed; however, marked improvement is likely even in patients with advanced immunosuppression. The increase in CD4 count indicates a corresponding decrease in 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's sarcoma) and opportunistic infections.

HAART aims to suppress viral replication to undetectable levels; this goal can usually be achieved 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 mutations in HIV that make viruses completely or partially resistant and make subsequent treatment more likely to fail.

Patients beginning HAART sometimes deteriorate clinically, despite increasing CD4 counts, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections. These sometimes serious reactions are termed immune reconstitution inflammatory syndromes (IRIS). IRIS can complicate many infections and even cancers (eg, Kaposi's sarcoma) but is usually self-limited or responds to treatment with brief regimens of corticosteroids. Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires assessment of the persistence of active infection with cultures and can be difficult.

The success of HAART is assessed by measuring plasma HIV RNA levels every 4 to 8 wk for the first 4 to 6 mo or until HIV levels are undetectable (ie, < 50 copies/mL) and every 3 to 6 mo thereafter. Increasing levels are the earliest evidence of treatment failure and may precede a decreasing CD4 count by months. Maintaining patients on failing drug regimens contributes to development of HIV mutants that are more drug-resistant; however, compared with wild-type HIV, these mutants appear to reduce the CD4 count less.

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. 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 (which is susceptible) because resistant mutants replicate more slowly. 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.

Several classes of antiretrovirals are used in HAART (see Table 4: Human Immunodeficiency Virus (HIV): Antiretroviral Drugs ). There are 5 classes of antiretrovirals; 3 of them inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

Table 4
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Antiretroviral Drugs  Generic name Abbreviation Usual Adult Dosea Some Adverse Effectsb Entry (fusion) inhibitors Enfuvirtide T-20 90 mg sc bid Hypersensitivity reactions, local injection site reactions Maraviroc (CCR5 inhibitor) — 150–600 mg bid, depending on other drugs used Myocardial ischemia or infarction Vicrivirocc (CCR5 inhibitor) — — — Integrase inhibitors Raltegravir — 400 mg bid None Non-nucleoside reverse transcriptase inhibitors Rash (occasionally severe or life threatening), liver dysfunction Delavirdine DLV 400 mg tid Inhibits cytochrome P-450 metabolism of indinavir Possibly serious effects if delavirdine is given with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, Ca channel blockers, ergot alkaloid preparations, amphetamines, or cisapride Efavirenz EFV 600 mg at bedtime CNS symptoms, false-positive cannabinoid test results, excessive blood levels if the drug is taken after fatty meals Etravirine — 200 mg bid Rashes Nevirapine NVP 200 mg once/day for 2 wk, then 200 mg bid Increased cytochrome P-450, reducing levels of protease inhibitors Nucleoside reverse transcriptase inhibitors Lactic acidosis, liver damage Abacavir ABC 300 mg bid Severe hypersensitivity reactions (especially during rechallenge), anorexia, nausea, vomiting Didanosine ddI 400 mg once/day or 200 mg bid if ≥ 60 kg 250 mg once/day or 125 mg bid if < 60 kg Peripheral neuropathyd, pancreatitise, diarrhea Emtricitabine FTC 200 mg once/day Minimal; skin hyperpigmentation Lamivudine 3TC 150 mg bid or 300 mg once/day Peripheral neuropathy, rarely pancreatitis Stavudine d4T 40 mg bid if ≥ 60 kg 30 mg bid if < 60 kg Peripheral neuropathy, rarely pancreatitis, fat redistribution with lipoatrophy of face and extremities Zalcitabine ddC 0.75 mg tid Peripheral neuropathy, pancreatitise, oral ulcers Zidovudine ZDV, AZT 300 mg bid Anemia and leukopeniaf, rarely pancreatitis, myositis Nucleotide reverse transcriptase inhibitor Tenofovir TDF 300 mg once/day Increased levels of ddI; otherwise minimal Protease inhibitorsg Nausea, vomiting, diarrhea, abdominal discomfort, increased serum glucose and hypercholesterolemia (common), increased abdominal fat, liver dysfunction, bleeding tendency (particularly in hemophiliacs) Amprenavir APV 1200 mg bid with food Rash Atazanavir ATV 400 mg once/day Hyperbilirubinemia Darunavir — 600 mg bid, taken with ritonavir 100 mg bid and with food Severe rash, fever Fosamprenavir None 1400 mg bid Rash Indinavir IND 800 mg tid on an empty stomach (600 mg for patients taking DLV; should not be given with ddI) Kidney stones, occasionally obstructive (patients should ingest 1300 mL of fluid daily) Cross-resistance with other protease inhibitors, especially ritonavir Lopinavir LPV 400 mg bid (in fixed combination with 100 mg ritonavir) with food Altered taste, circumoral paresthesias Nelfinavir NLF 1250 mg bid with food — Ritonavir RIT 600 mg bid with food Altered taste, circumoral paresthesias Possibly decreased incidence and severity of adverse effects with dose reduction Saquinavir SQV 1200 mg tid, within 2 h of a meal (trough levels and efficacy possibly increased when used with ritonavir) — Tipranavir TPV 500 mg with ritonavir 100 mg bid Hepatitis aDoses are given orally, unless otherwise specified. bAll 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. cVicriviroc is under study; it may be effective for patients who do not respond to enfuvirtide and other antiretrovirals. dPeripheral neuropathy may be reversible when the drug is stopped, and symptomatic treatment provides partial relief. eIf symptoms of pancreatitis (eg, nausea, vomiting, back and abdominal pain) occur, ddI or ddC must be immediately stopped until pancreatitis is confirmed or excluded. fAnemia 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). gAll are metabolized by the cytochrome P-450 system, creating potential for many drug interactions. Antiretroviral Drugs  Generic name Abbreviation Usual Adult Dosea Some Adverse Effectsb Entry (fusion) inhibitors Enfuvirtide T-20 90 mg sc bid Hypersensitivity reactions, local injection site reactions Maraviroc (CCR5 inhibitor) — 150–600 mg bid, depending on other drugs used Myocardial ischemia or infarction Vicrivirocc (CCR5 inhibitor) — — — Integrase inhibitors Raltegravir — 400 mg bid None Non-nucleoside reverse transcriptase inhibitors Rash (occasionally severe or life threatening), liver dysfunction Delavirdine DLV 400 mg tid Inhibits cytochrome P-450 metabolism of indinavir Possibly serious effects if delavirdine is given with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, Ca channel blockers, ergot alkaloid preparations, amphetamines, or cisapride Efavirenz EFV 600 mg at bedtime CNS symptoms, false-positive cannabinoid test results, excessive blood levels if the drug is taken after fatty meals Etravirine — 200 mg bid Rashes Nevirapine NVP 200 mg once/day for 2 wk, then 200 mg bid Increased cytochrome P-450, reducing levels of protease inhibitors Nucleoside reverse transcriptase inhibitors Lactic acidosis, liver damage Abacavir ABC 300 mg bid Severe hypersensitivity reactions (especially during rechallenge), anorexia, nausea, vomiting Didanosine ddI 400 mg once/day or 200 mg bid if ≥ 60 kg 250 mg once/day or 125 mg bid if < 60 kg Peripheral neuropathyd, pancreatitise, diarrhea Emtricitabine FTC 200 mg once/day Minimal; skin hyperpigmentation Lamivudine 3TC 150 mg bid or 300 mg once/day Peripheral neuropathy, rarely pancreatitis Stavudine d4T 40 mg bid if ≥ 60 kg 30 mg bid if < 60 kg Peripheral neuropathy, rarely pancreatitis, fat redistribution with lipoatrophy of face and extremities Zalcitabine ddC 0.75 mg tid Peripheral neuropathy, pancreatitise, oral ulcers Zidovudine ZDV, AZT 300 mg bid Anemia and leukopeniaf, rarely pancreatitis, myositis Nucleotide reverse transcriptase inhibitor Tenofovir TDF 300 mg once/day Increased levels of ddI; otherwise minimal Protease inhibitorsg Nausea, vomiting, diarrhea, abdominal discomfort, increased serum glucose and hypercholesterolemia (common), increased abdominal fat, liver dysfunction, bleeding tendency (particularly in hemophiliacs) Amprenavir APV 1200 mg bid with food Rash Atazanavir ATV 400 mg once/day Hyperbilirubinemia Darunavir — 600 mg bid, taken with ritonavir 100 mg bid and with food Severe rash, fever Fosamprenavir None 1400 mg bid Rash Indinavir IND 800 mg tid on an empty stomach (600 mg for patients taking DLV; should not be given with ddI) Kidney stones, occasionally obstructive (patients should ingest 1300 mL of fluid daily) Cross-resistance with other protease inhibitors, especially ritonavir Lopinavir LPV 400 mg bid (in fixed combination with 100 mg ritonavir) with food Altered taste, circumoral paresthesias Nelfinavir NLF 1250 mg bid with food — Ritonavir RIT 600 mg bid with food Altered taste, circumoral paresthesias Possibly decreased incidence and severity of adverse effects with dose reduction Saquinavir SQV 1200 mg tid, within 2 h of a meal (trough levels and efficacy possibly increased when used with ritonavir) — Tipranavir TPV 500 mg with ritonavir 100 mg bid Hepatitis aDoses are given orally, unless otherwise specified. bAll 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. cVicriviroc is under study; it may be effective for patients who do not respond to enfuvirtide and other antiretrovirals. dPeripheral neuropathy may be reversible when the drug is stopped, and symptomatic treatment provides partial relief. eIf symptoms of pancreatitis (eg, nausea, vomiting, back and abdominal pain) occur, ddI or ddC must be immediately stopped until pancreatitis is confirmed or excluded. fAnemia 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). gAll are metabolized by the cytochrome P-450 system, creating potential for many drug interactions.

• 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.

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 factors such as concomitant conditions (eg, hepatic 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 in treating women and children change regularly and are updated at www.aidsinfo. nih.gov.Interactions between antiretrovirals may synergistically 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, increasing the other drug's levels and 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, 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 can decrease activity of some antiretroviral drugs and should be avoided.

Adverse effects

Antiretrovirals can have serious adverse effects (see Table 4: Human Immunodeficiency Virus (HIV): Antiretroviral Drugs ). Some of these effects, notably anemia, pancreatitis, hepatitis, 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 damage, and renal function), especially when 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 distal extremities to the trunk 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. Hyperlipidemia and hyperglycemia due to insulin resistance may occur with lipodystrophy. Drugs from all classes appear to contribute to these metabolic effects. Some, such as ritonavir or d4T, do so commonly; others, such as atazanavir, appear to have 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 HAART 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 HAART is usually safe if all drugs are stopped simultaneously. 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.

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 HAART 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 Medicolegal Issues: 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.

Prevention

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

Prevention of transmission

Vaginal microbicides (including antiretroviral drugs) inserted before sexual contact have 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 Table 2: Human Immunodeficiency Virus (HIV): HIV Transmission Risk of 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, 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: If pregnant women test positive for HIV, risk of maternal-fetal transmission should be explained (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Prevention of perinatal transmission). Monotherapy with ZDV or nevirapine reduces risk by two thirds, and 2- or 3-drug combination therapy probably reduces it even more. Some drugs can be toxic to the fetus or mother and cannot be guaranteed to prevent transmission. If treatment is indicated, combination therapy tailored to the woman's history and stage of pregnancy should be used throughout pregnancy. Cesarean delivery can reduce risk of transmission. Some women choose to terminate their pregnancy for this or other reasons.
• Screening of blood and organs: Transmission by blood transfusion is still possible 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.
• Antiretrovirals: Giving antiretrovirals to HIV-infected people reduces risk of transmission, but how much risk is reduced is unclear.
• Circumcision of men: In several African countries, circumcision reduced incidence by about 50%; it is probably also effective elsewhere.
• 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.

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 fluids. Other body fluids of concern include

• Semen
• Vaginal secretions
• Body fluids obviously contaminated with blood

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:

• Nature and time of the exposure
• Clinical information, including risk factors and serologic tests for HIV, about the source patient for the exposure and the person exposed

Nature of the exposure is defined by

• Which body fluid was involved
• Whether exposure involved a penetrating injury (eg, needlestick, cut with sharp object)
• 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 hollow-bore needle with visible blood, 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 is about 0.3% after percutaneous exposure and about 0.09% after mucous membrane exposure.

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 Table 5: Human Immunodeficiency Virus (HIV): Postexposure Prophylaxis Recommendations).

Table 5
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Postexposure Prophylaxis Recommendations Infection Status of Source Prophylaxis HIV-positive class 1* 2-drug PEP for less severe exposure† 3-drug PEP for more severe exposure‡ HIV-positive class 2§ 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 No PEP warranted *Class 1: Asymptomatic HIV infection or known low viral load (< 1500 RNA copies/mL). † 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. §Class 2: Symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load. ¶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 50 (RR11): 1–42, June 29, 2001.

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 www.cdc.gov/mmwr/ PDF/rr/rr5011.pdf or www.nccc.ucsf.edu/about_nccc/pepline/.

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 Preventing Opportunistic Infections Among HIV-Infected Persons.)

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: Prophylaxis against P. jirovecii pneumonia and toxoplasmic encephalitis 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 < 75/μL: Prophylaxis against disseminated MAC with azithromycin, clarithromycin, or rifabutin is recommended. 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, high-risk exposure, or prior history of infection), regardless of CD4 count, patients should be given either rifampicin 10 mg/kg po up to 600 mg or rifabutin 300 mg po daily plus either pyrazinamide 25 mg/kg po up to 2.5 g for 2 mo or isoniazid 5 mg/ kg po up to 300 mg 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 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 Fungi: Treatment).
• Latent toxoplasmosis: This disorder 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.
• P. jirovecii pneumonia (see Pneumonia: Pneumocystis jirovecii Pneumonia)
• Herpes simplex infection (see Herpesviruses: Herpes Simplex Virus (HSV) Infections)
• Aspergillosis (possibly—see Fungi: Aspergillosis)

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

Vaccination

Vaccination (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 and varicella (secondary boosting with varicella-zoster, consisting of high-titer live virus) would potentially be valuable in HIV-infected adults, and both are undergoing testing. But their safety needs to be evaluated because these live-virus vaccines are potentially dangerous for patients with severe immunosuppression. For children with HIV infection, vaccination recommendations vary (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Vaccination and see Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Considerations for Use of Live Vaccines in Children With HIV Infection).

Last full review/revision January 2009 by J. Allen McCutchan, MD, MSc