- Clinical science
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'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.
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.
- US: ∼ 1.2 million
- Global: ∼ 37 million
Epidemiological data refers to the US, unless otherwise specified.
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
- Risk for male-to-female sex
- 0.1% for female partner
- 0.05% for male partner
- 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
- Risk per sexual act
Risk of transmission can be lowered significantly if HIV infection is treated consistently and viral load is below the limit of detection!
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 )
Natural history of HIV infection
Initial infection and HIV replication cycle
- 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)
- Viral envelope fuses with host cell, capsid enters the cell.
- For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.
- Patients without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygous CCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).
- Virion's RNA is transcribed into DNA; and then integrated into the host's DNA
- Viral DNA is replicated and virions are assembled
- 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
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 surface molecules in infected cells
- 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.
- Myalgia and arthralgia
- Generalized nontender lymphadenopathy
- Generalized rash
- Gastrointestinal symptoms (nausea, diarrhea, weight loss)
- Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing)
Clinical latency and AIDS
- Patients may still be asymptomatic
- Chronic subfebrile temperatures
- Persistent generalized lymphadenopathy
- Localized opportunistic infections (e.g., oral candidiasis , vaginal infections )
- Oral hairy leukoplakia (lesions located mainly on the lateral borders of the tongue)
- Chronic diarrhea (> 1 month)
- Skin manifestations (e.g. molluscum contagiosum, warts; , exacerbations of psoriasis, shingles)
- AIDS: see learning card on
Test patients with a history of injecting drugs who present with otherwise unexplained weight loss, depression, and/or dementia 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
Clinical category B
Clinical category C
|(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
WHO (World Health Organization) classification
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 (≥ 36.7°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/μL) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
- Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma)
- 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
- Combination antigen/antibody tests; : detect both HIV antigen (p24) and anti-HIV antibodies → a negative result essentially rules out HIV infection (almost 100% sensitivity)
- 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.
- 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
- Neonatal HIV infection
- Patients with indeterminate results
- Patients presenting before seroconversion
- Screening of blood donors
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
- Viral RNA load: indicator of ART response
Additional laboratory studies
- CBC: possibly lymphocytopenia
- General approach: all persons infected with HIV (regardless of CD4 count) should begin combined antiretroviral therapy (cART) as soon as possible.
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' to 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.
- Bone marrow suppression → neutropenia, anemia
- Mitochondrial toxicity → myopathy, neuropathy, hepatic steatosis, and lactic acidosis
- Abacavir-related hypersensitivity syndrome
- Didanosine/stavudine: pancreatitis
- HIV-associated lipodystrophy: abnormal distribution of fat (clinical presentation varies greatly)
- Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene)
- Mechanism of action: NRTIs act as nucleoside analogs → prevent the formation of 3' to 5' phosphodiester linkages → inhibit reverse transcription of RNA to DNA
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:
- Mechanism of action: non-competitive inhibitors of viral reverse transcriptase
- Nucleotide analogs (also called nucleotide reverse-transcriptase inhibitors; NtRTI): e.g., tenofovir
Protease inhibitors (PI): e.g., indinavir, ritonavir, nelfinavir, lopinavir
- Mechanism of action: inhibition of viral protease → inability to cleave viral polypeptides → generation of viral proteins impaired → only immature (non-infectious) virions are produced
- Side effects:
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
- 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
- Recommended regimens
See the learning card on
We list the most important complications. The selection is not exhaustive.
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 continue to have high CD4 counts for long periods
- Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months)
- The average life expectancy of HIV-infected patients who receive adequate antiretroviral treatment is 15–20 years lower than noninfected individuals of the same age.
- Individual prognosis depends on various factors, including:
- 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
- Let the wound bleed.
- Rinse/flush with water and soap and/or antiseptic agent.
- Immediately seek medical attention.
- If occupational exposure: report incident immediately.
- Efficacy of immunization is reduced in HIV-infected individuals (due to impaired immune function)
- The should be observed with the exception that: live-attenuated influenza, varicella zoster, and MMR vaccines should not be given if CD4 count < 200 cells/μl (CD4 percentage < 15% in patients ≤ 5 years) or if AIDS-defining conditions are present. The inactivated polio vaccine should be used instead of the live-attenuated polio vaccine.
- Immunizations that are not part of the standard immunization schedule:
- Highest risk during birth (perinatal vertical transmission)
- Prenatal transmission is possible
- Risk depends on maternal viral load
Reducing risk of transmission
- Combined antiretroviral therapy (cART) is recommended throughout pregnancy
- Delivery method
- Viral load > 1,000 copies/mL (or unknown) near time of delivery: increased risk of HIV transmission
- Viral load and mother has received cART during pregnancy: low risk of HIV transmission
- Breastfeeding should generally be avoided , because risk of transmission is 5–20% .
- Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA