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(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.
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Sidebar 1
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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
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Table 1
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| Clinical Categories of HIV Infection* |
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Category
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Disorder or Symptoms
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A
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Asymptomatic
Persistent generalized adenopathy
Symptoms of acute primary HIV infection
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B
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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
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C
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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
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*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.
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†Added in the 1993 expansion of the AIDS surveillance case definition.
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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
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.
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Table 2
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| HIV Transmission Risk of Several Sexual Activities |
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Risk
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Activity
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None (unless sores are present)
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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
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Theoretical (extremely low risk unless sores are present)
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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
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Low
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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
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High
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Vaginal or anal intercourse with or without ejaculation if a condom is not used or is not used correctly
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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:
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.
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:
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:
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:
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.
Diagnosis
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:
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:
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
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.
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:
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:
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:
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
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 of the exposure is defined by
Risk of infection is categorized as high or low:
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).
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Table 5
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| Postexposure Prophylaxis Recommendations |
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Infection Status of Source
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Prophylaxis
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HIV-positive
class 1*
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2-drug PEP for less severe exposure†
3-drug PEP for more severe exposure‡
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HIV-positive
class 2§
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3-drug PEP
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Unknown HIV status of source or unknown source
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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
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HIV-negative
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No PEP warranted
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*Class 1: Asymptomatic HIV infection or known low viral load (< 1500 RNA copies/mL).
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† Less severe exposure may involve a solid needle or superficial injuries.
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‡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.
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§Class 2: Symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load.
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¶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.
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PEP = postexposure prophylaxis.
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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.
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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/Hotlines/PEPline.html.
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:
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:
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
Content last modified January 2009
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