Harrison's Practice

HIV, AIDS

Definition

  • HIV disease
    • An infectious disease caused by HIV, a human retrovirus
    • HIV disease should be viewed as a spectrum ranging from primary infection, with or without an acute symptomatic mononucleosis-like syndrome, to an asymptomatic stage, to advanced disease characterized by profound immunodeficiency and susceptibility to opportunistic infections.
  • AIDS
    • Advanced stage of infection with HIV
    • Current case definition
      • Any HIV-infected person with a CD4+ T-cell count < 200/μL
      • Development of an AIDS-defining clinical condition (See Classification.)

Epidemiology

  • Prevalence worldwide
    • A global pandemic, with cases reported from virtually every country
    • 33.2 million individuals were living with HIV infection (range: 30.6–36.1 million) as of the end of 2007.
      • In the early stages of the pandemic, the majority of patients were male; now ~50% are female.
      • 2.5 million are children < 15 years.
      • More than 95% of people living with HIV/AIDS reside in low- and middle-income countries.
      • Two-thirds of all people with HIV infection (~22.5 million) live in sub-Saharan Africa.
      • In Asia, an estimated 4.9 million people were living with HIV at the end of 2007.
      • In Eastern Europe and Central Asia, ~1.6 million people were living with HIV at the end of 2007.
      • In Latin America and the Caribbean, ~1.8 million people are living with HIV/AIDS .
      • In North America and in Western and Central Europe, ~2.1 million people are living with HIV/AIDS.
    • In 2007, there were an estimated 2.5 million new cases of HIV infection worldwide.
    • In 2007, global AIDS deaths totaled 2.1 million.
    • Through 2005, the cumulative number of AIDS-related deaths worldwide exceeds 25 million.
      • HIV/AIDS is the second leading infectious disease cause of death worldwide.
  • Prevalence in the U.S.
    • ~1.1 million people are living with HIV/AIDS.
      • One-quarter of these persons are unaware of their infection.
      • Estimated HIV seroprevalence rate among adults aged 15–49 years in the U.S. is ~0.6%.
      • Prevalence is highest among young adults in their late twenties and thirties and among minorities.
  • Incidence in the U.S.
    • The number of new infections per year is estimated to be ~52,000.
      • This number has remained stable for at least 15 years.
    • Among adults and adolescents newly diagnosed with HIV infection (regardless of AIDS status) in the U.S. in 2005
      • ~74% are men.
        • ~67% were due to male-to-male sexual contact.
        • ~15% to heterosexual contact
        • ~13% to injection drug use
        • ~5% to a combination of male-to-male sexual contact and injection drug use
      • ~26% are women.
        • ~80% were due to heterosexual contact.
        • ~20% to injection drug use
    • New diagnoses of HIV/AIDS
      • Proportion of newly reported cases of AIDS among men who have sex with men has declined from ~64% of cases diagnosed in 1985 to ~42% of cases diagnosed in 2005.
      • Proportion of new AIDS cases attributed to heterosexual contact has increased dramatically, from 3% in 1985 to 31% in 2005.
      • AIDS diagnoses due to injection drug use was 19% in 1985, peaked at 31% in 1993, and was 21% in 2005.
      • Women are increasingly affected; the proportion of AIDS cases among female adults and adolescents (age >13 years) increased from 7% in 1985 to 27% in 2005.
  • Distribution (U.S.)
    • Most cases of transmission by injection drug use and heterosexual transmission are reported from the Northeast and Southeast, particularly among minority groups.
    • HIV infection and AIDS have disproportionately affected minority groups in the U.S.
      • Among those diagnosed with HIV (regardless of AIDS status) in 2005
        • 49% percent were African Americans (a group that comprises only 13% of the U.S. population)
        • Estimated 3% of black men and 1% of black women in their thirties are living with HIV infection.
        • HIV/AIDS ranked ninth among all causes of mortality in the U.S in 2004 among those aged 35–64 years, but among African Americans, it ranked third.
    • The estimated rates of AIDS diagnoses per 100,000 persons among adults and adolescents in 2004 were:
      • 72.1 for African Americans
      • 25.0 for Hispanics
      • 7.1 for whites
      • 9.9 for American Indians/Alaska Natives
      • 4.4 for Asian/Pacific Islanders

Risk Factors

  • Sexual transmission
    • Homosexual and heterosexual contact with an infected person
    • In U.S.
      • 49% of new HIV/AIDS diagnoses in 2005 among adults and adolescents were attributed to male-to-male sexual contact.
      • 32% of new HIV/AIDS diagnoses in 2005 among adults and adolescents were attributed to heterosexual contact.
    • Worldwide
      • Heterosexual transmission is the most common mode of infection.
    • Male-to-female transmission is usually more efficient than female-to-male transmission.
      • Small numbers of HIV-positive female index partners limit conclusive sex-specific estimates of transmission probabilities per sex act.
    • Receptive anal intercourse is a much more efficient mode of transmission than oral sex.
    • The presence of other sexually transmitted diseases significantly increases the risk of transmission, especially those with genital ulceration.
    • Lack of circumcision carries an increased risk of HIV infection.
    • The association of alcohol consumption and illicit drug use with unsafe sexual behavior leads to an increased risk of sexual transmission of HIV.
    • Methamphetamine (“crystal meth,” “tina”) and other so-called club drugs (e.g., ecstasy, ketamine, and gamma hydroxybutyrate), sometimes taken in conjunction with sildenafil (Viagra) or related drugs, have been associated with risky sexual practices and increased risk of HIV infection, particularly among men who have sex with men.
    • Use of oral contraceptives
      • Some studies showed an association of oral contraceptive use with an increase in incidence of HIV infection over and above that which might be expected by not using a condom for birth control.
        • May be due to drug-induced changes in the cervical mucosa, rendering it more vulnerable to penetration by the virus
    • Adolescent girls
      • Might be more susceptible to infection upon exposure due to the properties of an immature genital tract with increased cervical ectopy or exposed columnar epithelium
  • Transmission by blood and blood products
    • Transmission by HIV-tainted blood transfusions, blood products, or transplanted tissue
      • Currently estimated that the risk of infection with HIV in the U.S. via transfused screened blood is approximately 1 in 1.5 million donations.
    • Intravenous drug users
      • Exposed to HIV while sharing injection paraphernalia, such as needles, syringes, the water in which the drugs are mixed, or the cotton through which drugs are filtered
      • Does not require intravenous puncture
        • Subcutaneous (skin popping) or intramuscular (muscling) injections can transmit HIV.
  • Occupational transmission of HIV (health care workers and laboratory personnel)
    • Risk of HIV transmission after skin puncture from a needle or a sharp object that was contaminated with blood from a person with documented HIV infection is ~0.3%, and after a mucous membrane exposure it is 0.09%.
    • Transmission after nonintact skin exposure has been documented.
      • The risk is estimated to be less than the risk for mucous membrane exposure.
    • In addition, the following fluids are considered potentially infectious during occupational exposure:
      • Semen and vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid
        • However, risk for transmission after exposure to fluids or tissues other than HIV-infected blood is probably considerably lower than for blood exposures.
    • Risk of transmission from an infected health care worker to patients is extremely low in developed countries; in fact, too low to be measured accurately.
  • Maternal-fetal/infant transmission
    • Can be transmitted intrapartum, perinatally (most commonly), or via breast milk
    • In the absence of prophylactic antiretroviral therapy to the mother during pregnancy, labor, and delivery, and to the fetus following birth, the probability of transmission of HIV from mother to infant/fetus ranges from:
      • 15–25% in industrialized countries
      • 25–35% in developing countries
    • Higher rates of transmission have been reported to be associated with many factors, the best documented of which is the presence of high maternal levels of plasma viremia.
    • Prolonged interval between membrane rupture and delivery is another well-documented risk factor for transmission.
  • Transmission by other body fluids
    • Although the virus can be identified from virtually any body fluid, there is no evidence that HIV can be transmitted as a result of exposure to following fluids unless they are visibly bloody:
      • Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus
    • Transmission of HIV by a human bite can occur but is rare.

Etiology

Human retroviruses HIV-1 and HIV-2

  • Family of human retroviruses (Retroviridae)
  • Subfamily of lentiviruses
  • RNA viruses whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase
  • HIV-1 is the most common cause of AIDS worldwide.
  • HIV-2 has been identified predominantly in western Africa.
    • Small numbers of cases have also been reported in Europe, South America, Canada, and the U.S.
    • Has ~40% sequence homology with HIV-1
    • More closely related to simian immunodeficiency viruses

Transmission

  • See Risk Factors.
  • Sexual contact: heterosexual and homosexual
  • Contact with blood, blood products, or other bodily fluids (as in drug abusers who share contaminated intravenous needles)
  • Intrapartum or perinatally from mother to infant or via breast milk
  • Contact with HIV-infected specimens (a definite but small occupational risk of infection for health care workers and laboratory personnel)

Pathophysiology and immunopathogenesis

  • Hallmark of HIV disease is a profound immunodeficiency.
  • Results from a progressive deficiency of the subset of T lymphocytes (CD4+ T cells), referred to as helper or inducer T cells
    • The CD4 molecule serves as the primary cellular receptor for HIV.
    • A co-receptor must be present with CD4 for efficient entry of HIV-1 into target cells.
    • The 2 major co-receptors for HIV-1 are CCR5 and CXCR4.
  • Although the CD4+ T lymphocyte and CD4+ monocyte lineage are the principal cellular targets of HIV, virtually any cell that expresses CD4 along with 1 of the co-receptors can potentially be infected by HIV; however, infection, if it occurs in these other cell types is not efficient.

Primary infection

  • After initial transmission, the virus infects CD4+ cells, probably T lymphocytes, monocytes, or bone marrow–derived dendritic cells.
  • Most patients undergo a viremic stage during primary infection.
    • In some, this is associated with the "acute retroviral syndrome," a mononucleosis-like illness.
    • Virus is disseminated to lymphoid and other organs throughout the body.
      • Gut-associated lymphoid tissue (GALT) is a primary and early target of infection and memory CD4+ T cell depletion.
    • Infection is ultimately contained partially by the development of an HIV-specific immune response and the trapping of virions in lymphoid tissue.

Establishment of chronic and persistent infection

  • Despite the robust immune response following primary infection, virus is not cleared from the body.
    • Instead, a chronic infection develops that persists for a median of 10 years before the patient becomes clinically ill.
  • During this variable period of clinical latency
    • The number of CD4+ T cells gradually decreases.
    • Few, if any, clinical findings are evident.
    • Active viral replication can almost always be detected by measurable plasma viremia and the demonstration of virus replication in lymphoid tissue.
  • Level of steady-state viremia (referred to as the viral set point) at approximately 1 year after infection
    • Has important prognostic implications for the progression of HIV disease
    • Persons with a low viral set point at 6 months to 1 year after infection progress to AIDS more slowly than those whose set point is very high at this time.

Advanced HIV disease

  • When CD4+ T-cell counts fall below a critical level (~200/µL), patients become highly susceptible to a variety of opportunistic diseases.
  • Control of plasma viremia by effective antiretroviral therapy
    • Can increase survival even in persons with extremely low CD4+ T-cell counts even though CD4+ T-cell counts may not increase significantly as a result of therapy

Symptoms & Signs

Acute HIV syndrome

  • 50–70% of persons with HIV infection experience an acute clinical syndrome approximately 3–6 weeks after primary infection.
  • Usually persists for 1 to several weeks
  • General
    • Fever
    • Pharyngitis
    • Lymphadenopathy (70% of cases)
    • Headache/retro-orbital pain
    • Arthralgias/myalgias
    • Lethargy/malaise
    • Anorexia
    • Weight loss
    • Nausea
    • Vomiting
    • Diarrhea
  • Neurologic
    • Meningitis
    • Encephalitis
    • Peripheral neuropathy
    • Myelopathy
  • Dermatologic
    • Erythematous maculopapular rash
    • Mucocutaneous ulceration

Asymptomatic infection

  • The length of time between infection and development of disease varies, but the median is ~10 years.
  • Active viral replication continues during this asymptomatic period, and CD4+ T-cell counts decrease.

Symptomatic disease

  • Symptoms can develop at any time during the course of HIV infection.
    • The spectrum of illness generally changes as the CD4+ T-cell count decreases.
    • More severe and life-threatening complications of HIV infection occur in patients with a CD4+ T-cell count < 200/μL.
  • Major clinical syndromes seen in the symptomatic stage of HIV infection are summarized below.
  • Persistent generalized lymphadenopathy
    • Palpable adenopathy at ≥ 2 extrainguinal sites that persists for > 3 months without explanation other than HIV infection
  • Constitutional symptoms
    • Fever persisting for > 1 month
    • Involuntary weight loss of > 10% of baseline
    • Diarrhea for > 1 month in absence of explainable cause
  • Neurologic disease
    • HIV encephalopathy (AIDS dementia complex): most common
    • Opportunistic infections
    • Primary central nervous system (CNS) lymphoma
    • CNS Kaposi’s sarcoma
    • Aseptic meningitis
    • Myelopathy
    • Peripheral neuropathy
    • Myopathy
  • Secondary infectious diseases
  • Secondary neoplasms
    • Kaposi’s sarcoma (cutaneous and visceral, more fulminant course than in non–HIV-infected patients)
    • Lymphoid neoplasms (especially B cell lymphomas of brain, marrow, GI tract)
  • Organ-specific disease
    • A variety of organ-specific manifestations and complications can be seen, either as primary manifestations of the HIV infection or as complications of treatment (see Complications).

Differential Diagnosis

Diagnostic Approach

  • The U.S. Centers for Disease Control and Prevention (CDC) has recommended that screening for HIV infection be performed as a matter of routine health care.
  • Diagnosis of HIV infection
    • Diagnosis depends on demonstration of antibodies to HIV and/or direct detection of HIV or 1 of its components.
    • Antibodies to HIV appear 2–12 weeks after infection.
  • Initial evaluation of patient with HIV infection
    • History and physical examination
    • Routine chemistry and hematology
    • Lipid profile and fasting glucose
    • Pap smear
    • Chest x-ray
    • CD4+ T-lymphocyte count
    • 2 plasma HIV RNA levels
    • HIV resistance testing
    • Rapid plasma reagin test
    • Anti-Toxoplasma antibody titer
    • Purified protein derivative skin test
    • Mini-Mental Status Examination
    • Serologies for hepatitis A, B, and C
    • Immunization with pneumococcal polysaccharide; influenza as indicated
    • Immunization with hepatitis A and hepatitis B if seronegative
    • Counseling regarding natural history and transmission
    • Helping contact others who might be infected
  • Diagnosis of AIDS
    • CD4+ T-cell count < 200/μL or
    • AIDS-defining clinical condition (See Classification.)

Laboratory Tests

Diagnosis of HIV infection

  • See Figure 1 for the algorithm of serologic testing.
  • Enzyme immunoassay (EIA) (enzyme-linked immunosorbent assay)
    • Standard screening test for HIV infection
    • The test is highly sensitive (>99.5%).
      • Most commercial EIA kits can detect antibodies to both HIV-1 and -2.
      • Fourth-generation EIA tests combine detection of antibodies to HIV with detection of the p24 antigen of HIV.
      • In rare instances, an HIV-infected individual treated early in the course of infection may revert to a negative EIA.
        • This does not indicate clearing of infection.
        • It signifies levels of ongoing exposure to virus insufficient to maintain a measurable antibody response.
        • When these individuals have discontinued therapy, viruses and antibodies have reappeared.
    • Test not optimally specific, therefore confirmatory test needed
      • False-positive results can occur with:
        • Antibodies to class II antigens
        • Autoantibodies
        • Hepatic disease
        • Recent influenza vaccination
        • Acute viral infections
  • Western blot
    • Most commonly used confirmatory test
    • Detects antibodies to HIV antigens of specific molecular weights
    • Antibodies to HIV begin to appear within 2 weeks of infection.
    • Period of time between initial infection and development of detectable antibodies is rarely > 3 months.
  • Tests for direct detection of HIV
    • These tests are useful in:
      • Patients with a positive or indeterminate EIA result and an indeterminate Western blot result or
      • Patients in whom serologic testing may be unreliable (such as those with hypogammaglobulinemia)
    • Immune complex dissociated p24 antigen capture assay
      • Plasma p24 antigen levels increase during the first few weeks following infection, before the appearance of anti-HIV antibodies.
    • HIV RNA by polymerase chain reaction
    • HIV RNA by branched DNA
    • HIV RNA by nucleic acid sequence-based assay
  • Point-of-care tests
    • OraQuick Rapid HIV-1 antibody test (among the most popular of these)
      • Can be run on blood, plasma, or saliva
      • Sensitivity and specificity of this test are each ~99%.
      • Negative results from this test are adequate to rule out a diagnosis of HIV infection.
      • Positive finding should be considered preliminary and confirmed with standard serologic testing.

Other tests at diagnosis

  • Complete blood count
  • Chemistry profile
  • Aminotransferase measurement
  • Blood urea nitrogen and creatinine measurement
  • Urinalysis
  • Pap smear
  • Fasting blood glucose and serum lipid measurement

Monitoring HIV infection and response to therapy

  • CD4+ T-cell count
    • Generally accepted indicator of immunologic competence
    • Close relationship between the CD4+ count and clinical manifestations of AIDS
      • < 200/µL: high risk of infection with Pneumocystis
      • < 50/µL: high risk for CMV disease and infection with Mycobacterium avium intracellulare and/or T. gondii
    • Should be measured
      • At the time of diagnosis
      • Every 3–6 months thereafter
      • Measurements may be done more frequently in patients with decreasing counts.
    • Antiretroviral therapy
      • A CD4+ T-cell count < 350/µL is an indication to start therapy according to most practice guidelines.
  • HIV RNA level
    • Predicts what will happen to the CD4+ T cell count in the near future and may itself be correlated with immune dysfunction
    • Should be measured
      • At the time of HIV diagnosis
      • Every 3–4 months thereafter in the untreated patient
    • Useful in making therapeutic decisions about antiretroviral therapy
      • After initiation of therapy or any change in therapy, HIV RNA levels should be monitored approximately every 4 weeks until the effectiveness of the therapeutic regimen is determined by development of a new steady-state level of HIV RNA.
      • During therapy, levels of HIV RNA should be monitored every 3–4 months to evaluate the continuing effectiveness of therapy.
  • HIV resistance testing
    • Sensitivity of patient’s HIV virus(es) to different antiretroviral agents can be tested by genotypic or phenotypic assays.
    • In the hands of experts, the use of resistance testing enhances the short-term ability to achieve ~0.5-log decreases in viral load compared to changing drugs merely on the basis of drug history.
    • Helps in the selection of new drugs in patients with virologic failure
    • May also be of value in selecting an initial regimen for treatment of therapy-naïve individuals, particularly in geographic areas with a high level of background resistance
  • Co-receptor tropism assay
    • Used to determine whether or not a patient’s virus is likely to respond to CCR5 antagonist (e.g., maraviroc) treatment
      • Patients tend to have CCR5-tropic virus early in the course of infection.
    • Two commercial assays are available.
      • Trofile assay (Monogram Biosciences)
      • Phenoscript assay (VIRalliance)
    • These assays take weeks to perform and are expensive.

Imaging

  • Directed by specific HIV complications

Diagnostic Procedures

  • See Diagnostic Approach and Laboratory Tests.

Classification

Clinical categories of HIV infection

Category A

  • ≥1 of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection; conditions seen in B and C must not have occurred
    • Asymptomatic HIV infection
    • Persistent generalized lymphadenopathy
    • Acute (primary) HIV infection with accompanying illness or history of acute HIV infection

Category B (symptomatic)

  • Symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C and that meet ≥ 1 of the following criteria:
    • Conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity or
    • Conditions are considered by physicians to have a clinical course or to require management complicated by HIV infection
  • Examples include, but are not limited to:
    • Bacillary angiomatosis
    • Candidiasis, oropharyngeal (thrush)
    • Candidiasis, vulvovaginal: persistent, frequent, or poorly responsive to therapy
    • Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
    • Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting > 1 month
    • Hairy leukoplakia, oral
    • Herpes zoster (shingles), involving ≥ 2 distinct episodes or > 1 dermatome
    • Idiopathic thrombocytopenic purpura
    • Listeriosis
    • Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
    • Peripheral neuropathy

Category C (AIDS)

  • Conditions listed in the AIDS surveillance case definition
    • Candidiasis of bronchi, trachea, or lungs
    • Candidiasis, esophageal
    • Cervical cancer, invasive
    • Coccidioidomycosis, disseminated or extrapulmonary
    • Cryptococcosis, extrapulmonary
    • Cryptosporidiosis, chronic intestinal (>1 month’s duration)
    • CMV disease (other than liver, spleen, or nodes)
    • CMV retinitis (loss of vision)
    • Encephalopathy (HIV-related)
    • Herpes simplex: chronic ulcer(s) (> 1 month’s duration) or bronchitis, pneumonia, or esophagitis
    • Histoplasmosis, disseminated or extrapulmonary
    • Isosporiasis, chronic intestinal (> 1 month’s duration)
    • Kaposi’s sarcoma
    • Lymphoma, Burkitt’s (or equivalent term)
    • Lymphoma, primary, of brain
    • M. avium complex, or Mycobacterium kansasii, disseminated or extrapulmonary
    • Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
    • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
    • P. jiroveci (formerly P. carinii) pneumonia
    • Pneumonia, recurrent
    • Progressive multifocal leukoencephalopathy
    • Salmonella septicemia, recurrent
    • Toxoplasmosis of brain
    • Wasting syndrome due to HIV

Treatment Approach

Principles of therapy of HIV infection

  • Ongoing HIV replication leads to immune system damage and progression to AIDS.
  • Plasma HIV RNA levels indicate the magnitude of HIV replication and the rate of CD4+ T-cell destruction.
  • CD4+ T-cell counts indicate the current level of competence of the immune system.
  • Rates of disease progression differ among patients, and treatment decisions should be individualized based primarily CD4+ T-cell counts as well as level of plasma HIV RNA.
  • Maximal suppression of viral replication is a goal of therapy; the greater the suppression, the less likely the appearance of drug-resistance quasispecies.
  • The most effective therapeutic strategies involve simultaneous initiation of combinations of anti-HIV drugs active against the patient’s virus.
  • The antiretroviral drugs used in combination regimens should be used according to optimum schedules and dosages.
  • The number of available drugs is limited; any decisions on antiretroviral therapy have a long-term impact on future options for the patient.
  • Women should receive optimal antiretroviral therapy regardless of pregnancy status. During first trimester, be aware of teratogenic potential of certain drugs.
  • Compliance is an important part of ensuring maximal effect from a given regimen.
    • The simpler the regimen, the easier it is for the patient to be compliant.

Indications for initiation of antiretroviral therapy

  • Acute infection syndrome (no clear consensus)
  • Chronic infection
    • Symptomatic disease
    • Asymptomatic diseases
      • CD4+ T-cell count < 350/μL or decreasing
      • Pregnancy
      • This is an area of controversy; some experts would:
        • Wait until the CD4 cell count declines to 200/μL
        • Treat everyone with a viral load >100,000 copies/mL
        • Treat everyone regardless of CD4+ T cell count
        • Bottom line is that risk benefit ratio of therapeutic approach regarding when to start therapy during the asymptomatic stage should be discussed between physician and patient.
  • Postexposure prophylaxis
    • 6-week course of therapy to uninfected individuals immediately following a high-risk exposure to HIV

Indications for changing antiretroviral regimens

  • < 1-log decrease in plasma HIV RNA by 4 weeks after initiation of therapy
  • A reproducible significant increase (defined as 3-fold or greater) from the nadir of plasma HIV RNA level not attributable to intercurrent infection, vaccination, or test method
  • Persistently decreasing CD4+ T-cell count
  • Clinical deterioration
  • Side effects
  • Unless contraindicated for reasons of toxicity, patients started on antiretroviral therapy should remain on antiretroviral therapy.
    • While it seems reasonable to assume that the complications associated with antiretroviral therapy could be minimized by regimens designed to minimize exposure to the drugs in question, all efforts to do so have paradoxically been associated with an increase in serious adverse events in the patients randomized to intermittent therapy suggesting that some “non-AIDS”–associated serious adverse events such as heart attack and stroke may be linked to HIV replication.

Treatment prophylaxis considerations based on CD4+ count

  • < 200/μL
    • P. jiroveci prophylaxis
  • < 50/μL
    • Primary prophylaxis for M. avium infection

Specific Treatments

Antiretroviral therapy

Virologic failure during treatment

  • Virologic failure is currently defined as:
    • HIV RNA level > 400 copies/mL after 24 weeks
    • >50 copies/mL after 48 weeks
    • Repeated HIV RNA level > 400 copies/mL after prior suppression of viremia to < 400 copies/mL
  • Evaluation of antiretroviral treatment failure should include:
    • Assessing the severity of HIV disease
    • Antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance/toxicity
    • Results of prior drug-resistance testing
  • Drug-resistance testing
    • Should be done while the patient is taking the failing antiretroviral regimen (or as soon as possible within 4 weeks of treatment discontinuation)
  • Managing virologic failure
    • Use the treatment history and past and current resistance test results to identify active agents (preferably at least 2 fully active agents) to design a new regimen.
    • A fully active agent is one likely to demonstrate antiretroviral activity on the basis of both the treatment history and susceptibility on drug-resistance testing.
    • If at least 2 fully active agents cannot be identified:
      • Consider pharmacokinetic enhancement of protease inhibitors (with the exception of nelfinavir) with ritonavir and/or
      • Reuse other prior antiretroviral agents to provide partial antiretroviral activity
    • Significant antiretroviral activity can be obtained by adding to an optimized background antiretroviral regimen.
      • A drug with activity against drug-resistant virus (e.g., a potent ritonavir-boosted PI)
      • A drug with a new mechanism of action (e.g., HIV entry inhibitor)
    • One active drug should not be added to a failing regimen because drug resistance is likely to develop quickly.
      • However, in patients with advanced HIV disease (e.g., CD4+ T-cell count < 100/μL) and high risk of clinical progression, adding 1 active agent (with an optimized background regimen) may provide clinical benefits and should be considered.

Prevention of opportunistic infections

Primary and secondary prophylaxis

  • See Table 182-8 for details regarding these and other opportunistic organisms.
  • P. jiroveci
    • Indications
      • CD4 count < 200/μL or
      • Oropharyngeal candidiasis or
      • Unexplained fever for >2 weeks or
      • Prior bout of P. jiroveci pneumonia
      • May stop prophylaxis if CD4+ T-cell count > 200/μL for 3 months
    • First choice
      • Trimethoprim–sulfamethoxazole, 1 double-strength tablet qd
  • M. tuberculosis
    • Indications
      • Skin test > 5 mm or
      • Prior positive test without treatment or
      • Positive interferon-γ release assay or
      • Close contact with case of active tuberculosis
    • First choices
    • If drug resistance is suspected, check with local public health authorities.
  • M. avium complex
    • Indications
      • CD4 count < 50/μL
      • Prior documented disseminated disease
      • May stop prophylaxis if CD4+ T-cell count > 100/μL for 3 months
    • First choice

Immunizations recommended

  • See Table 182-8 for details.
  • Hepatitis B virus
    • Indications
      • All susceptible (anti–hepatitis B core antigen and anti–hepatitis B surface antigen negative) patients
  • Hepatitis A virus
    • Indications
      • All susceptible (anti–hepatitis A virus negative) patients
  • Influenza virus
    • Indications
      • All patients annually
  • Streptococcus pneumoniae
    • Indications
      • All patients, preferably before CD4+ T cell count ≥200/μL
  • Human papilloma virus
    • Indications
      • Girls and women 9–26 years of age

Recommendations for prevention of severe and frequent recurrences

  • See Table 182-8 for details.
  • Herpes simplex
  • Candida
    • Indications
      • Frequent/severe recurrences
    • First choice

Monitoring

  • CD4+ T-cell counts
    • Measure every 3–6 months after diagnosis.
      • Measurements may be done more frequently in patients with decreasing counts.
      • CD4 T-cell count < 350/μL is an indication for consideration of initiating antiretroviral therapy.
      • Decline in CD4+ T-cell count of >25% is an indication for considering a change in therapy.
    • < 200/µL: high risk for infection with P. jiroveci
    • < 50/µL: at high risk of infection with CMV, M. avium complex, and/or T. gondii
    • In patients with hypersplenism or who have undergone splenectomy, the CD4+ T-cell percentage may be a more reliable indication of immune function than the CD4+ T-cell count.
      • CD4+ T-cell percent of 15 is comparable to a CD4+ T-cell count of 200/μL.
  • Plasma HIV RNA levels
    • Useful in making decisions about antiretroviral therapy
    • In untreated patients
      • Measure every 3–6 months after diagnosis.
    • Most guidelines suggest that therapy be considered in patients with >100,000 copies of HIV RNA per milliliter
    • After initiation or any change in therapy
      • Monitor about every 4 weeks until effectiveness is determined by development of new steady-state level of HIV RNA.
    • During chronic therapy
      • Monitor every 3–4 months to evaluate the continuing effectiveness of therapy.
  • HIV-resistance testing
    • Drug-resistance testing in the setting of virologic failure should be performed while the patient is still on the failing regimen.
      • Due to propensity for the pool of HIV quasispecies to rapidly revert to wild-type in the absence of the selective pressure of antiretroviral therapy

Complications

General

Diseases of the respiratory system

Diseases of the cardiovascular system

Diseases of the oropharynx and GI system

Hepatobiliary disease

  • Hepatitis B
  • Hepatitis C
  • Granulomatous hepatitis
  • Hepatic masses
  • Biliary tract disease
    • Papillary stenosis
    • Sclerosing cholangitis
  • Liver injury due to drug toxicity
  • Pancreatic injury due to drug toxicity

Diseases of the kidney and genitourinary tract

  • HIV-associated nephropathy
  • Drug-induced renal damage
  • Genitourinary tract infections
  • Infections with Treponema pallidum
  • Vulvovaginal candidiasis
  • Vaginitis

Diseases of the endocrine system and metabolic disorders

  • Lipodystrophy
    • Elevated triglyceride level
    • Elevated total cholesterol level
    • Elevated lipoprotein B level
    • Hyperinsulinemia
    • Hyperglycemia
    • Approximately 20% of the patients with HIV-associated lipodystrophy meet the criteria for the metabolic syndrome.
  • Avascular necrosis of the hips and shoulders
  • Osteoporosis/osteopenia
  • Lactic acidosis
  • Hyponatremia
  • Hypothyroidism
  • Hypogonadism

Rheumatologic diseases

Immune reconstitution inflammatory syndrome

  • Characteristics
    • Paradoxical worsening of clinical condition following the initiation of antiretroviral therapy
    • Occurs weeks to months following the initiation of antiretroviral therapy
    • Most common in patients starting therapy with a CD4+ T-cell count under 50/μL who experience a precipitous drop in viral load
    • Frequently seen in the setting of tuberculosis
    • Can be fatal

Diseases of the hematopoietic system

  • Lymphadenopathy
  • Anemia
  • Leukopenia
  • Neutropenia
  • Thrombocytopenia
  • Persistent generalized lymphadenopathy
  • Venous thrombotic events
  • Abnormalities of the coagulation cascade have been reported.
    • Decreased protein S activity
    • Increases in factor VIII
    • Presence of anticardiolipin antibodies

Dermatologic diseases

Neurologic diseases

Ophthalmologic disease

  • Cotton-wool spots
  • CMV retinitis
  • Progressive outer retinal necrosis syndrome
  • Pneumocystis jiroveci (formerly P. carinii)
  • Toxoplasmosis

Additional disseminated infections and wasting syndrome

  • Bacillary angiomatosis
  • Histoplasmosis
  • Penicillum marneffei infection
  • Visceral leishmaniasis
  • Malaria
  • Generalized wasting
  • CNS Chagas’ disease

Neoplastic diseases

  • Kaposi’s sarcoma
  • Non-Hodgkin lymphoma
  • Primary CNS lymphoma
  • Cervical, brain, testicular, oral, lung, and anal cancers
  • Hodgkin’s disease, multiple myeloma, leukemia, melanoma
  • Multicentric Castleman’s disease
    • HHV-8 associated lymphoproliferative disorder
    • Not a true malignancy
    • Prior to the availability of highly active antiretroviral therapy, HIV-infected patients with multicentric Castleman’s disease had a 15-fold increased risk of developing non-Hodgkin’s lymphoma compared with HIV-infected patients in general.

Prognosis

  • The median time from primary HIV infection to the development of AIDS in untreated persons in the developed world is ~10 years.
    • This period has been markedly extended by the wide availability of combinations of antiretroviral drugs.
  • Mortality
    • In 2003, HIV infection was the sixth leading cause of death among Americans 25–44 years of age in the U.S.
    • The annual number of AIDS-related deaths in the U.S. decreased ~70% from 1995 to 2003.
    • Currently, ~5 deaths annually per 100,000 persons
  • Approximately 60% of deaths among patients with AIDS are a direct result of an infection other than HIV, primarily:
    • Viral hepatitis
    • Other non-AIDS-defining bacterial infections
  • Fewer than 50% of deaths among AIDS patients are as a direct result of an AIDS-defining illness.
    • The average CD4+ T-cell count of an HIV-infected patient at the time of death is just over 300 cells/μL.
    • Incidence of secondary infections has decreased dramatically following the widespread use of:
      • Combination antiretroviral therapy and
      • Implementation of guidelines for the prevention of opportunistic infections
    • In addition to the classic AIDS-defining illnesses, patients with HIV infection also have an increase in serious non-AIDS illnesses, including cardiovascular, renal, and hepatic disease.

Prevention

  • The U.S. Centers for Disease Control and Prevention has recently recommended:
    • HIV testing become part of routine medical care
    • All individuals between the ages of 13 and 64 years be informed of the testing and be tested without the need for written informed consent
    • Individual could “opt out” of testing, but if he or she does not, testing would be routinely administered.
  • Cornerstones of prevention
    • Education
    • Counseling
    • Behavior modification
      • Abstinence or practicing safer sex (condoms together with the spermatocide nonoxynol-9)
      • Stopping the use of injectable drugs or using sterilized needles and no sharing of drug paraphernalia
        • Studies are underway to determine the safety and efficacy of preexposure as well as postexposure administration of antiretroviral drugs for the prevention of HIV infection.
  • Screening of blood products
    • Risk of transmission by transfusion has reduced to 1 in 1.5 million donations.
    • Autologous blood donation is a better choice, if possible.
    • Screening of all blood donors for HIV infection by assays for both HIV antibody and p24 antigen and self-referral of persons at risk for HIV infection
    • Clotting factor concentrates are heat treated, essentially eliminating the risk to hemophiliacs who require these products.
  • Screening of donors for:
    • Artificial insemination
    • Tissues used in organ transplantation
  • Use of universal precautions by all health care workers when caring for all patients
  • Perinatal transmission of HIV
    • Rate of mother-to-child transmission is approaching 1% or less in pregnant women who are receiving combination antiretroviral therapy for their HIV infection.
    • Such treatment, combined with cesarean section delivery, has rendered mother-to-child transmission of HIV an unusual event in the U.S. and other developed nations.
    • In developed countries, current recommendations to reduce perinatal transmission of HIV include:
      • Universal voluntary HIV testing and counseling of pregnant women
      • Antiretroviral prophylaxis with ≥ 1 drugs in cases in which the mother does not require therapy for her HIV infection
      • Combination therapy for women who do require therapy
      • Obstetric management to minimize exposure of the infant to maternal blood and genital secretions
      • Avoidance of breast-feeding
    • Short-course antiretroviral regimens have now been used for several years in developing nations for the prevention of mother-to-child transmission where full treatment regimens for pregnant women are not readily available.
      • Short-course prophylactic antiretroviral regimens (e.g., single dose of nevirapine given to the mother at the onset of labor and a single dose to the infant within 72 hours of birth)
      • Antiretroviral therapy is currently available to only ~25% of persons in developing nations who require it.
  • Vaccines
    • Development of a safe and effective HIV vaccine is the object of active investigation.
    • Extensive animal work is ongoing, and clinical trials of candidate vaccines are underway in humans.

ICD-9-CM

  • 042 Human immunodeficiency virus [HIV] disease
  • V08 Asymptomatic human immunodeficiency virus [HIV] infection status (includes HIV positive, not otherwise specified)

See Also

Internet Sites

General Bibliography

  • Benson CA et al: Treating opportunistic infections among HIV-exposed and infected children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep 53(RR-15):1, 2004
  • Brenner BG et al: High Rates of Forward Transmission Events after Acute/Early HIV-1 Infection. J Infect Dis 195:951, 2007  [PMID:17330784]
  • Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 2005;17 (Revised ed), 2007. Available at http://www.cdc.gov/hiv/
  • Centers for Disease Control and Prevention: Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep 55(RR-14):1, 2006
  • Centers for Disease Control and Prevention (CDC): Trends in HIV/AIDS diagnoses--33 states, 2001-2004. MMWR Morb Mortal Wkly Rep 54:1149, 2005  [PMID:16292247]
  • Chun TW, Fauci AS: Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci U S A 96:10958, 1999  [PMID:10500107]
  • Davey RT et al: HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 96:15109, 1999  [PMID:10611346]
  • Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents:Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, October 10, 2006. Updates available at http://www.aidsinfo.nih.gov
  • Dybul M et al: Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm Rep 51(RR-7):1, 2002. Updates available at http://www.aidsinfo.nih.gov
  • Esté JA, Telenti A: HIV entry inhibitors. Lancet 370:81, 2007  [PMID:17617275]
  • Fauci AS: Host factors and the pathogenesis of HIV-induced disease. Nature 384:529, 1996  [PMID:8955267]
  • Fauci AS: The AIDS epidemic--considerations for the 21st century. N Engl J Med 341:1046, 1999  [PMID:10502595]
  • Geretti AM: Epidemiology of antiretroviral drug resistance in drug-naïve persons. Curr Opin Infect Dis 20:22, 2007  [PMID:17197878]
  • Grinspoon S, Carr A: Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352:48, 2005  [PMID:15635112]
  • Haase AT: Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 5:783, 2005  [PMID:16200081]
  • Hammer SM: Clinical practice. Management of newly diagnosed HIV infection. N Engl J Med 353:1702, 2005  [PMID:16236741]
  • Hammer SM et al: Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 296:827, 2006  [PMID:16905788]
  • Hoffman RM, Currier JS: Management of antiretroviral treatment-related complications. Infect Dis Clin North Am 21:103, 2007  [PMID:17502232]
  • Kaplan JE et al: Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 51(RR-8):1, 2003. Updates available at http://www.aidsinfo.nih.gov
  • Lipman M, Breen R: Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 19:20, 2006  [PMID:16374213]
  • Lopez Bernaldo de Quiros JC et al: A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med 344:159, 2001  [PMID:11172138]
  • May MT et al: HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet 368:451, 2006  [PMID:16890831]
  • Mofenson LM et al: U.S. Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR Recomm Rep 51(RR-18):1, 2002. Updates available at http://www.aidsinfo.nih.gov
  • Nabel GJ: Challenges and opportunities for development of an AIDS vaccine. Nature 410:1002, 2001  [PMID:11309631]
  • Panel on Clinical Practices for Treatment of HIV: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, October 6, 2005. Available at http://AIDSinfo.nih.gov.
  • Pantaleo G, Koup RA: Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat Med 10:806, 2004  [PMID:15286782]
  • Quinn TC et al: Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 342:921, 2000  [PMID:10738050]
  • Simon V, Ho DD, Abdool Karim Q: HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 368:489, 2006  [PMID:16890836]
  • Stevenson M: HIV-1 pathogenesis. Nat Med 9:853, 2003  [PMID:12835705]
  • U.S. Public Health Service: Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep 50(RR-11):1, 2001. Updates available at http://www.aidsinfo.nih.gov
  • UNAIDS: AIDS epidemic update: December 2005. Available at http://www.unaids.org
  • This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 182, Human Immunodeficiency Virus Disease: AIDS and Related Disorders, by AS Fauci and HC Lane.

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HIV, AIDS
Last updated: August 25, 2008
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