• Clinical science

Human immunodeficiency virus

Abstract

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 CD4+ lymphocytes (especially T cells) and so impairs 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's sarcoma) and/or a CD4 count < 200 cells/μL. 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. Although there have been significant advances in treatment, the average life expectancy of HIV patients remains 15–20 years lower than that of healthy individuals of the same age.

Epidemiology

  • 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.

Etiology

Pathogen (human immunodeficiency virus)

  • Lymphotropic lentivirus (from the family of retroviridae)
  • Consists of the two species HIV-1 and HIV-2
    • HIV-1: most common species worldwide
    • HIV-2: restricted almost completely to West Africa

Routes of transmission

  • Sexual: responsible for ∼ 80% of infections worldwide
    • Risk per sexual act
      • Risk for men who have sex with men (MSM): 0.5% for receptive partner
        • 0.06% for insertive partner
        • 0.01% for receptive partner in oral sex
      • Risk for male-to-female sex
        • 0.1% for female partner
        • 0.05% for male partner
        • 0.5% for receptive partner in anal sex
    • Modifying factors
      • Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml
      • Circumcision: reduced risk of infection for circumcised men
      • Coinfection: genital inflammation (e.g., as a result of coinfection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission
      • Genital mucosal damage: increases risk of transmission
  • Parenteral
    • Needle sharing: 0.67% per exposure through needle-sharing contact
    • Needlestick injuries: 0.36% per injury
    • Infectious blood on mucous membranes: 0.1% per exposure
    • Blood transfusions: 0.00005% risk per transfusion (1 in 2 million)
  • Vertical
    • During childbirth (∼ 5–15%)
    • Through breastfeeding after birth (∼ 5–20%)

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

References:[4][2][5][6][7][8][9][10][11]

Pathophysiology

Structure of HIV

  • Physical structure: icosahedral with a spiked envelope
  • Genome : 9 genes encoding a total of 15 proteins (e.g., reverse transcriptase , integrase , and envelope proteins )
    • pol gene codes for a polyprotein that consists of protease, reverse transcriptase, and integrase
    • gag gene codes for gag protein, which consists of matrix protein, nucleocapsids, and capsid proteins
    • env gene codes for surface glycoproteins, gp41 and gp120

Natural history of HIV infection

  • Initial infection and HIV replication cycle
    1. HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on target cells with its gp120 glycoprotein (binding)
    2. Viral envelope fuses with host cell, capsid enters the cell.
    3. Virion's RNA is transcribed into DNA and then integrated into the host's DNA
    4. Viral DNA is replicated and virions are assembled
    5. Virion repurposes a portion of the cell's membrane as envelope and leaves the cell (budding) → cell death
  • Progression to chronic immunodeficency
    • HIV infects CD4+ lymphocytes, then reproduces and spreads to other CD4+ lymphocytes near the original site of infection → infection of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and dissemination → acute HIV syndrome with high viral load
    • After the acute stage, viral load decreases and remains at roughly that level for approximately 8–10 years (clinical latency stage )
    • → loss of CD4+ lymphocytes (especially T cells) impairs immune function and thereby facilitates opportunistic infections and development of malignancies (AIDS) → these secondary diseases are usually the cause of death in patients with HIV
    • Increased viral load generally leads to a decreased number of CD4+ lymphocytes and vice versa, but the relation is not linear.

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

Acute HIV syndrome does not develop in all patients! The hallmark of HIV is chronic persistent infection!

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:[4][2][5][12]

Clinical features

General considerations

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

Acute HIV infection

  • Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome.
  • Fever
  • Fatigue
  • Myalgia and arthralgia
  • Headache
  • Generalized nontender lymphadenopathy
  • Generalized rash
  • Gastrointestinal symptoms (nausea, diarrhea, weight loss)
  • Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing)

Clinical latency and AIDS

Test patients with a history of injecting drugs who present with otherwise unexplained weight loss, depression, and/or dementia for HIV!

Candidiasis in the esophagus, unlike oral candidiasis, is an AIDS-defining condition!

References:[4][13][12][14][15]

Stages

CDC classification system for HIV

CDC categories of HIV are based on CD4 count in combination with current or previously diagnosed HIV-related conditions. These stages indicate disease progression and prognosis. Any patient belonging in categories A3, B3 or C1-C3 is considered to have AIDS.

CD4 cell count category

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/μL A1 B1 C1
(2) 200–499 cells/μL A2 B2 C2
(3) < 200 cells/μL A3 B3 C3

PGL= Persistent generalized lymphadenopathy

References:[5]

Diagnostics

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 : regular testing (e.g., annually)
  • One-time testing is recommended early in every pregnancy
  • HIV-testing requires patient consent (opt-out)

Initial diagnostic approach

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

  • Screening tests
    • Combination antigen/antibody tests; (fourth generation tests) : detect both HIV antigen (p24) and anti-HIV antibodies → a negative result essentially rules out HIV infection (almost 100% sensitivity)
    • Antibody-only tests
      • 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 : can detect both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the two types
    • Western blot: tests may be negative 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 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
  • Post-treatment monitoring
    • Viral RNA load: indicator of ART response
      • Decrease in viral loads indicates effective treatment
      • Prognostic marker in long-term treatment
    • CD4+ count: correlates with overall immune function
    • CD4+:CD8+ ratio: Used in the immunological evaluation of long-term follow-up cases
      • Expected increase in ratio with successful ART therapy
      • Correlates with immune dysfunction and viral reservoir size

Additional laboratory studies

  • CBC: possibly lymphocytopenia
  • Liver enzymes: not initially affected by HIV
    • If liver enzymes are abnormal, rule out coinfection with hepatitis virus (HCV or HBV)

References:[16][17][18][19][20]

Treatment

Antiretroviral HIV therapy

Antiretroviral drugs

  • Nucleoside reverse transcriptase inhibitors (NRTI): e.g., zidovudine, lamivudine, emtricitabine, abacavir, stavudine, didanosine
    • Mechanism of action: NRTIs act as nucleoside analogs → prevent the formation of 3'→5' phosphodiester linkages → inhibit reverse transcription of RNA to DNA
      • NRTIs require intracellular phosphorylation for activation, and their efficacy is thus reliant on kinase availability and activity, which is variable depending on cell functionality and activation state.
    • Side effects
    • Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene)
  • Non-nucleoside reverse-transcriptase inhibitors (NNRTI): e.g., nevirapine, efavirenz
    • Mechanism of action: non-competitive inhibitors of viral reverse transcriptase
      • NNRTIs do not require intracellular phosphorylation for activation, but are direct inhibitors
    • Side effects:
  • Nucleotide analogs (also called nucleotide reverse-transcriptase inhibitors; NtRTI): e.g., tenofovir
  • Protease inhibitors (PI): e.g., indinavir, ritonavir, nelfinavir, lopinavir
  • Integrase inhibitors (INI): e.g., raltegravir, dolutegravir
    • Mechanism of action: inhibition of the viral integrase .
  • Fusion inhibitor: enfuvirtide
    • Mechanism of action: competitively binds to the viral protein gp41 and thereby prevents fusion with the cell
  • CCR5-antagonist: maraviroc
    • Mechanism of action: blocks the CCR5 coreceptor that is essential to cell infection for some HIV genotypes (R5 viruses)
    • Not generally recommended because of comparatively high costs and limited clinical data

Regimens

  • Recommended regimens
    • 3 NRTI (e.g., zidovudine, lamivudine, abacavir) OR
    • 2 NRTI (e.g., lamivudine + abacavir) AND
      • 1 NNRTI (e.g., efavirenz) OR
      • 1 PI (e.g., lopinavir) OR
      • 1 INI (e.g., raltegravir)
  • Combinations that should be avoided

Hepatotoxic drugs (e.g. nevirapine) are contraindicated if there is coinfection with HBV or HCV!

Most NRTIs end in “-ine”, protease inhibitors in “-avir”, and integrase inhibitors end in “-gravir!”

References:[4][8][18][21][22][23][24][25][26]

Complications

See the learning card on HIV-associated conditions

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

Prognosis

  • Morbidity and mortality among patient subsets
    • Untreated HIV infection has a mortality rate of > 90% (average time from infection to death approx. 8–10 years)
    • 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 keep high CD4 counts for long periods
    • Average life expectancy of HIV-infected patients who receive adequate antiretroviral treatment is 15–20 years lower compared to noninfected individuals of the same age.
  • 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

References:[5][27]

Prevention

HIV post-exposure prophylaxis

  • Indications
    • Injury with HIV-contaminated instruments or needles
    • Contamination of open wounds or mucous membranes with HIV-contaminated fluids
    • Unprotected sexual activity with a known or potentially HIV-infected person
  • Timing: Initiate as soon as possible (ideally within one to two hours after exposure)
  • Drugs: A three-drug regimen is recommended (similar to cART treatment). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor:
  • Measures after needle stick injury or other contamination
    1. Let the wound bleed
    2. Rinse/flush with water and soap and/or antiseptic agent
    3. Immediately seek medical attention
    4. If occupational exposure: report incident immediately
  • Obligation to notify authorities: injuries and cuts from objects that are (potentially) contaminated need to be reported to OSHA on OSHA 300

Vaccinations in HIV-infected individuals

References:[8][28][29][30][31][32]

Special patient groups

HIV in pregnancy

  • Transmission
    • Highest risk during birth (perinatal vertical transmission)
    • Prenatal transmission is possible
    • Risk depends on maternal viral load
  • Reducing risk of transmission
  • 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 parent!

References:[10][33][34][35]