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Human immunodeficiency virus

Last updated: September 15, 2021

Summarytoggle arrow icon

Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern which ultimately results in chronic immunodeficiency. HIV can be transmitted sexually, parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common in the young adult population between 20 and 30 years of age. The virus infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells and thereby impairing one of the key mechanisms of cellular immune defense. There are three major stages: acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS). For clinical staging, detailed classifications have been established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). During the stage of acute infection, the virus reproduces rapidly in the body, which can lead to acute, nonspecific (e.g., flu-like) symptoms (also known as acute retroviral syndrome, ARS) within 2–4 weeks. However, approximately half of all infected individuals remain asymptomatic. Once the stage of acute infection subsides, the clinical latency stage begins. Again, many individuals remain asymptomatic during this period, while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia). The last stage, AIDS, is characterized by AIDS-defining conditions (e.g., Kaposi sarcoma) and/or a CD4 count < 200 cells/mm3. HIV infection can reliably be detected via antigen/antibody-based tests. In patients with confirmed infection, the most important parameters for monitoring the disease are CD4 count and viral load. HIV treatment involves a combination of antiretroviral drugs (combination antiretroviral therapy, cART). In addition, HIV-related complications (e.g., HIV wasting syndrome, opportunistic infections) will require management. There have been significant advances in treatment so that the average life expectancy of HIV patients receiving current antiretroviral drugs is approaching that of the general population.

  • Incidence (in the US)
    • HIV infection: peak incidence between ages 20 and 30 (∼ 35/100,000)
    • AIDS: peak incidence approx. age 45 (∼ 14/100,000)
    • Ethnicity: Incidence is significantly higher in the Black population than in other population groups.
  • Prevalence
    • US: ∼ 1.2 million
    • Global: ∼ 37 million

References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Pathogen (human immunodeficiency virus)

“Polly is a Really Important Person.”: the proteins coded by the pol gene are Reverse transcriptase, Integrase, and Protease.

Routes of transmission

Risk of transmission can be lowered significantly if HIV infection is treated consistently and viral load is below the limit of detection!

References:[2][8][9][10][11][12]

Natural history of HIV infection

Viral load predicts the rate of disease progression and CD4 count correlates with immune function.

Acute HIV syndrome does not develop in all patients. Absence of symptoms may delay diagnosis.

The role of immune response

  • Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection.
  • HIV evades immune control via:
    • Genetic mutation and recombination
    • Downregulation of MHC class I surface molecules in infected cells

References:[2][8][14][15]

General considerations

  • There are no clinical features specific to HIV infection
  • In early HIV infection, patients are often asymptomatic.
  • Incubation period: usually 2–4 weeks [14]
  • Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak: during AIDS-stage)

Acute HIV infection [8][16]

Clinical latency and AIDS

Test patients with a history of intravenous drug use who present with otherwise unexplained weight loss, depression, and/or dementia for HIV.

Unlike oral candidiasis, esophageal candidiasis is an AIDS-defining condition.

References:[8][14][16]

CDC classification system for HIV [17]

  • CDC categories of HIV are based on CD4 count in combination with current or previously diagnosed HIV-related conditions.
  • Any patient belonging in categories A3, B3 or C1-C3 is considered to have AIDS.
CD4 cell count category
(normal cell count: 500-1500 cells/mm3)

Clinical category A

Asymptomatic, Acute HIV
or PGL

Clinical category B

Symptomatic conditions,
not A or C

Clinical category C

AIDS-defining conditions
(1) ≥ 500 cells/mm3 A1 B1 C1
(2) 200–499 cells/mm3 A2 B2 C2
(3) < 200 cells/mm3 A3 B3 C3

PGL= Persistent generalized lymphadenopathy

WHO (World Health Organization) classification [18]

WHO classifies individuals with confirmed HIV infection according to clinical features and diagnostic findings:

  • Primary HIV infection: acute retroviral syndrome or asymptomatic
  • Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
  • Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections
  • Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 37.6°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/mm3) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
  • Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma, Pneumocystis pneumonia)

HIV testing

Indications

  • Test all patients with clinical features of acute or chronic HIV infection
  • All individuals with possible past exposure, especially high-risk individuals (e.g., sex workers, men who have sex with men, IV drug users, partners of HIV-positive individuals): regular testing (e.g., annually)
  • One-time testing is recommended early in every pregnancy
  • HIV-testing requires patient consent (opt-out)

Initial diagnostic approach [19]

Both screening tests and confirmatory tests detect anti-HIV antibodies in the blood

  • Screening tests
    • Combination antigen/antibody tests (first-choice screening test)
    • Antibody-only tests (HIV serology)
      • ELISA (enzyme-linked immunosorbent assay): standard method for detecting antibodies within approx. 1–3 hours; requires laboratory
      • Rapid tests: can deliver results in ∼ 20 minutes and do not require a laboratory, which makes them suitable as an alternative to the more complex tests in some outpatient settings.
  • Confirmatory tests
    • HIV-1/HIV-2 antibody differentiation immunoassay; (first-choice confirmatory test): can detect both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the two types
    • Western blot:
      • The CDC no longer recommends western blot tests for confirmation of HIV infection.
      • Tests may be negative for up to 2 months after infection.
      • Results are usually available after several days and HIV subtype O is not reliably detected.
  • Detection of viral RNA
    • Can measure the amount of viral RNA in the blood and detect HIV infection earlier than antibody/antigen-based tests, but FDA-approved tests are limited to HIV-1
    • Indications
      • Neonatal HIV infection
      • Patients with indeterminate results
      • Patients presenting before seroconversion
      • Screening of blood donors
  • HIV drug resistance testing [20]
    • Indicated in newly diagnosed patients to determine drug resistance and appropriate therapy
    • Genotypic assays are preferred over phenotypic assays.
  • Post-treatment monitoring
    • Viral RNA load: indicator of ART response
      • Decrease in viral loads indicates effective treatment
      • Prognostic marker in long-term treatment (higher viral load → ↑ destruction of CD4+ lymphocytes → more severe immunodeficiency → worse prognosis)
    • CD4+ count: correlates with overall immune function
    • CD4+:CD8+ ratio: Used in the immunological evaluation of long-term follow-up cases [21]
      • Expected increase in ratio with successful ART therapy
      • Correlates with immune dysfunction and viral reservoir size

Additional laboratory studies

References:[22][23][24]

General approach [25]

Antiretroviral drugs [25]

Nucleoside reverse transcriptase inhibitors (NRTI)

To remember the nucleoside reverse transcriptase inhibitors “-vudine“, think: “The nuclear plant is in the vuds (read: “woods”)!”

Nonnucleoside reverse-transcriptase inhibitors (NNRTI)

HIV protease inhibitors (PI)

Integrase inhibitors (INI)

  • Examples of drugs
  • Mechanism of action: inhibition of the viral integrase → blockade of viral DNA integration into the host's DNA → inhibition of viral replication
  • Side effects: ↑ creatine kinase

Entry inhibitors [29]

  • Description: Hetereogenic class of antiretroviral drugs that inhibit binding or fusion of HIV virions with human cells.
  • Examples of drugs
    • Enfuvirtide (fusion inhibitor)
      • Mechanism of action: competitively binds to the viral protein gp41 and thereby prevents fusion with the cell
      • Side effects: skin irritation at the site of drug injection
    • Maraviroc (CCR5-antagonist)
  • Special indications : infection with drug-resistant HIV-1 [30]

To remember the mechanism of action of the fusion inhibitor enfuvirtide, think: “Enfuvirtide provides defusion of viral fusion.”

To remember the mechanism of action of maraviroc, think: “Maraviroc will block the viral dock.”

Regimens

Hepatotoxic drugs (e.g., nevirapine) are contraindicated in coinfection with HBV or HCV.

Most NRTIs end in “-ine,” protease inhibitors in “-navir,” and integrase inhibitors end in “-gravir.”

  • See the article on “HIV-associated conditions.”
  • Immune reconstitution inflammatory syndrome
    • Deterioriation of a preexisting opportunistic infection (e.g., PML, Kaposi sarcoma) within 60 days after initiation of HAART therapy
    • Thought to be caused by the restoration of immune function that results in inflammatory reactions at previously dormant sites of infection.
    • Occurs in 10–25% of patients with AIDS

We list the most important complications. The selection is not exhaustive.

  • Morbidity and mortality among patient subsets
    • Untreated, HIV leads to death on average 8–10 years after infection.
    • Progression varies among individuals: some patients may die within a few years while others remain asymptomatic for decades
      • Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months)
        • Some untreated individuals show only slow progression and can remain asymptomatic for more than 20 years.
        • In rare cases, untreated individuals have no detectable viremia and continue to have high CD4 counts for long periods
    • The average life expectancy of HIV-infected individuals who receive adequate antiretroviral treatment is approaching that of noninfected individuals of the same age. [31][32]
    • Individuals with HIV infection on adequate antiretroviral therapy are more likely to develop chronic comorbidities (e.g., cardiovascular disease, diabetes, cancer) than healthy individuals. [33][34]
  • Individual prognosis depends on various factors, including:
    • Adequate antiretroviral treatment
    • Viral set point and CD4 count
    • Exposure to opportunistic pathogens ,
    • Individual genetic properties
    • HIV species and subtype
    • Preexisting conditions

HIV pre-exposure prophylaxis [35]

HIV post-exposure prophylaxis [36]

References:[10][35][37][38][39][40][41]

HIV in pregnancy

  • Transmission
  • Antepartum and intrapartum management
    • Combined antiretroviral therapy (cART) is recommended throughout pregnancy and delivery.
    • The mode of delivery and the use of additional IV zidovudine depend on the maternal viral load during the intrapartum period; both of which must be considered to reduce the risk of transmission of HIV to the infant.
    • Zidovudine is also one of the few antiretroviral medications approved for HIV post-exposure prophylaxis in neonates.
Intrapartum management of HIV
Maternal viral load near time of delivery Delivery method Intrapartum antiretroviral treatment Infant prophylaxis
> 1000 copies/mL OR unknown viral load OR poor adherence to ARV treatment
50–1000 copies/mL
  • Low risk of HIV transmission
  • Vaginal delivery
  • IV zidovudine is administered based on an individualized decision.
≤ 50 copies/mL
  • Postpartum management
    • Postexposure prophylaxis in neonates: See “Infant prophylaxis” in the table above.
    • Breastfeeding should generally be avoided in countries with good food availability and hygienic baby food (e.g., clean drinking water) , because risk of transmission is 5–20% .
  • Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA

Suspect HIV in infants with failure to thrive, diffuse lymphadenopathy, diarrhea, and thrush, especially if the mother is a high-risk patient.

References:[7][42][43]

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