Human immunodeficiency virus

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)

• Family: Retroviridae
• Genus: Lentivirus
• Species
  • HIV-1: most common species worldwide
  • HIV-2: restricted almost completely to West Africa
• Structure: icosahedral with a conical capsid and a spiked envelope
• Genome
  • Psuedodiploid (2 RNA molecules yielding 1 DNA molecule)
  • 9 genes encoding a total of 15 proteins
• Function of structural proteins
  • pol gene codes for a polyprotein which consists of
    • Protease: cleavage of gag and gag-pol proteins during maturation of the virion ^[4]
    • Reverse transcriptase: converts viral RNA to dsDNA
    • Integrase: helps insert the viral genes into the host genome
  • gag gene codes for gag protein, which consists of
    • Matrix protein (p17 protein)
    • Nucleocapsids
    • Capsid proteins (p24 protein)
  • env gene codes for gp160 which gets cleaved into envelope glycoproteins
    • gp120: attaches to host CD4+ T-cells
    • gp41: assists in fusion and entry of the virus into the host cell

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

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 ^[5]
    • Circumcision: reduced risk of infection for circumcised men ^[6]
    • 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 transmission
  • 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 transmission: from mother to child
  • During childbirth (∼ 5–15%)
  • Through breastfeeding after birth (∼ 5–20%) ^[7]

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

• 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)
     • Cells that have CD4 receptors: T lymphocytes (e.g., T helper cells), macrophages, monocytes, dendritic cells.
  2. 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.
     • Viral entry into macrophages via CCR5 mainly occurs during the early stages of infection, while entry via CXCR4 occurs in later stages.
     • Individuals 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).
  3. A virion's RNA is transcribed into dsDNA by viral reverse transcriptase and then integrated into the host's DNA by viral integrase.
  4. Viral DNA is replicated and virions are assembled
  5. Virion repurposes a portion of the cell's membrane as an envelope and leaves the cell (budding) → cell death ^[13]
• Progression to chronic immunodeficiency
  • 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
    • Window period: The time between infection and detectability of HIV antibodies.
  • After the acute stage, viral load decreases and remains at roughly that level for approximately 8–10 years (clinical latency stage ).
  • During the clinical latency phase, the virus mainly replicates inside the lymph nodes.
  • Increasing 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 individuals 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 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 (1^st peak: within the first months after infection; 2^nd peak: during AIDS-stage)

Acute HIV infection ^[8][16]

• 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

• Clinical latency: Infected individuals may still be asymptomatic.
• Non-AIDS-defining conditions (common when CD4+ count is below 500 cells/mm³)
  • Chronic subfebrile temperatures
  • Persistent generalized lymphadenopathy
  • Chronic diarrhea (> 1 month)
  • Localized opportunistic infections
    • Oral candidiasis: creamy, white patches on the mucous membranes of the mouth that can be scraped off
    • Vaginal infections (e.g., yeast, trichomonads)
  • Oral hairy leukoplakia: lesions that cannot be scraped off located mainly on the lateral borders of the tongue; triggered by Epstein-Barr virus
  • HPV-related: squamous cell carcinoma of the anus (common in men who have sex with men) or cervix
  • Skin manifestations (e.g. molluscum contagiosum, warts; , exacerbations of psoriasis, shingles)
• AIDS: See article on “HIV-associated conditions.”

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.

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 (≥ 36.7°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)
    • Detect both HIV antigen (p24 capsid protein) and anti-HIV antibodies (IgG antibodies against HIV-1/HIV-2) → a negative result essentially rules out HIV infection (almost 100% sensitivity)
    • Not recommended for suspected neonatal HIV infection (results may be false-positive due to maternally transferred anti-HIV antibodies)
    • Viral RNA load test should be done in case of suspicion of perinatal HIV infection
  • 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+ counts increase in response to successful ART therapy
    • Critical measurement for initiating opportunistic infection prophylaxis
  • 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

• CBC: possibly lymphocytopenia
• Liver enzymes: if abnormal, rule out coinfection with hepatitis virus (HCV or HBV)

References:^[22][23][24]

General approach ^[25]

• All persons infected with HIV (regardless of CD4 count) should begin combined antiretroviral therapy (cART) as soon as possible
• Antiretroviral therapy should be prioritized in patients with:
  • Low CD4 count (< 350 cells/mm3) ^[26]
  • High viral load
  • Presence of AIDS-defining illness
• Therapy should be determined based on the HIV genotype
• Antiretroviral drugs are combined to prevent resistance (see “Regimens” below for details)
• All antiretroviral drugs are able to target both HIV-1 and HIV-2, except for enfuvirtide and NNRTIs

Antiretroviral drugs ^[25]

Nucleoside reverse transcriptase inhibitors (NRTI)

• Examples of drugs
  • Zidovudine (ZDV, formerly AZT)
  • Lamivudine (3TC)
  • Emtricitabine (FTC)
  • Abacavir (ABC)
  • Stavudine (d4T)
  • Didanosine (ddI)
  • Tenofovir (nucleotide analog, also called nucleotide reverse-transcriptase inhibitor; NtRTI)
• Mechanism of action
  • NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3' to 5' phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
  • Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
• Side effects
  • Bone marrow suppression: anemia (especially zidovudine), neutropenia
  • Mitochondrial toxicity
    • Myopathy
    • Peripheral neuropathy
    • Hepatic steatosis
    • Lactic acidosis
  • Abacavir-related hypersensitivity syndrome ^[27]
    • Potentially life-threatening systemic reaction with fever and maculopapular rash
    • Abacavir should be avoided in HLA-B*57:01-positive patients
  • Pancreatitis (didanosine/stavudine)
  • HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat
    • Loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities
    • Metabolic changes: impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL)
    • Probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump)
  • Tenofovir: nephrotoxicity ^[28]
    • Studies link tenofovir to proximal tubular dysfunction, acute tubular necrosis, and subsequent acute kidney injury.
    • Affected individuals show elevated creatinine, subnephrotic proteinuria, and glycosuria.
    • Acute tubular necrosis was confirmed via renal biopsy, which revealed enlarged, depleted, and dysmorphic mitochondria.
    • Discontinuation lead to significant recovery and suggests reversibility of the toxic tenofovir effects.
• Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene)

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

Nonnucleoside reverse-transcriptase inhibitors (NNRTI)

• Examples of drugs
  • Nevirapine
  • Efavirenz
  • Delavirdine
• Mechanism of action
  • Noncompetitive inhibitors of viral reverse transcriptase that bind to the reverse transcriptase at a different location than NRTIs
  • NNRTIs do not require intracellular phosphorylation for activation but are instead direct inhibitors.
• Side effects
  • Hepatotoxicity (nevirapine)
  • CNS toxicity and vivid or disturbing dreams (efavirenz)
  • Hypersensitivity reactions: rash, Stevens-Johnson syndrome

Protease inhibitors (PI)

• Examples of drugs
  • Indinavir
  • Ritonavir
  • Nelfinavir
  • Lopinavir
  • Atazanavir
  • Darunavir
  • Fosamprenavir
  • Saquinavir
• Mechanism of action: inhibition of viral HIV-1 protease (encoded by pol gene) → inability to cleave viral mRNA into functional units → generation of impaired viral proteins → production of immature (noninfectious) virions
• Side effects
  • GI upset (nausea, diarrhea)
  • Lipodystrophy and fat accumulation ,
  • Nephrolithiasis, crystal-induced nephropathy, and hematuria
  • Thrombocytopenia (indinavir)
  • Hyperglycemia: inhibition of insulin-dependent glucose transporters (GLUT 4) → peripheral insulin resistance → impaired glucose tolerance
• Special indications: Ritonavir can be used to increase concentrations of other drugs since it inhibits cytochrome P450.

Integrase inhibitors (INI)

• Examples of drugs
  • Raltegravir
  • Dolutegravir
  • Bictegravir
  • Elvitegravir
• 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)
    • Mechanism of action: blocks the CCR5 coreceptor on T cells and monocytes that is essential to cell infection; for some HIV genotypes (R5 HIV-1) → inhibits gp120 interaction → prevents virus docking
    • Side effects: hepatotoxicity, allergic reactions
• 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

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

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., diabetes, cancer) than healthy individuals. ^[33]
• 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 ^[34]

• Eligibility
  • Negative HIV test result and no signs or symptoms of acute HIV infection
  • Normal renal function test
  • Fulfillment at least one indication criteria
• Indications
  • Men who have sex with men
    • Any anal sex without condoms in the past 6 months
    • A bacterial STI (syphilis, chlamydia, or gonorrhea) diagnosed or reported in the past 6 months
  • Heterosexual men and women
    • Sexually active with an HIV positive partner
    • Inconsistent or no condom use during sexual activity with one or more sexual partners of unknown HIV status
    • A bacterial STI in the past 6 months
  • Intravenous drug users with high-risk needle behavior (e.g., sharing needles/equipment) or HIV positive injection partner
• Timing: Prior to the exposure to HIV and continued for a month after the exposure.
• Drugs
  • Emtricitabine + tenofovir disoproxil fumarate (TDF-FTC)
  • OR Emtricitabine + tenofovir alafenamide (TAF-FTC)
• Follow-up
  • HIV test every 3 months
  • Renal assessment at baseline and every 6 months
  • Counseling on adherence and risk reduction

HIV post-exposure prophylaxis ^[35]

• 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:
  • Tenofovir-emtricitabine + dolutegravir
  • Tenofovir-emtricitabine + raltegravir
• 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 the incident immediately.

References:^{[10][34][36][37][38][39][40]}

HIV in pregnancy

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

• 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][41][42]