HIV Infection and AIDS

Human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HIV), a single-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview belonging to the Retroviridae Retroviridae The human immunodeficiency virus (HIV) is a species of Lentivirus, a genus of the family Retroviridae, which causes HIV infections and acquired immunodeficiency syndrome (AIDS). The virus has high genetic variability and is divided into 2 major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). The human immunodeficiency virus is a single-stranded, positive-sense, enveloped RNA virus, which targets and destroys WBCs, leading to frequent opportunistic infections and, eventually, death. Retroviridae: HIV family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. The presentation is marked by constitutional symptoms such as lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Further progression predisposes to opportunistic infections and malignancies. Diagnosis is by enzyme immunoassay for HIV-1 and -2. Additional tests include HIV viral load, genotyping, and CD4+ T lymphocyte count to determine therapy and evaluate treatment response and disease progression. Immediate treatment with combination antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs is recommended.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology

Worldwide

  • At the end of 2018, there were approximately 37 million infected people.
  • Sub-Saharan Africa: 
    • The most affected area in the world
    • Approximately > 10% of adults aged 15–49 years are affected.
    • Accounts for > 50% of total global human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HIV) infections
Population infected with hiv in 2017

2017 world map of HIV infections (in people aged 15 to 49 years of age):
The colors indicate the percent of population with human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HIV) infection in each country. The information regarding the corresponding percent of population (designated color) is below the world map.

Image: “Share of the population infected with HIV, 2017” by Our World in Data. License: CC BY 4.0

United States

  • Approximately 38,700 new cases diagnosed each year
  • Approximately 1.1 million individuals currently living with HIV
  • HIV infection highest among Hispanics and African Americans (likely due to socioeconomic factors)
  • Gay and bisexual males account for most newly diagnosed cases.
  • Children usually acquire infection from their mother in utero or via subsequent breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding.

Etiology and Transmission

HIV

  • Genus, Lentivirus; family, Retroviridae Retroviridae The human immunodeficiency virus (HIV) is a species of Lentivirus, a genus of the family Retroviridae, which causes HIV infections and acquired immunodeficiency syndrome (AIDS). The virus has high genetic variability and is divided into 2 major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). The human immunodeficiency virus is a single-stranded, positive-sense, enveloped RNA virus, which targets and destroys WBCs, leading to frequent opportunistic infections and, eventually, death. Retroviridae: HIV
  • Structure:
    • Virion envelope contains 2 membrane glycoproteins:
      • Gp41 (transmembrane)
      • Gp120 (surface/docking protein)
    • Matrix protein p17: surrounds the virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview core
    • Virus core: 
      • Capsid protein p24
      • 2 single-stranded, enveloped positive-sense ribonucleic acid ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure) molecules coated with nucleocapsid protein
      • Enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (reverse transcriptase, integrase, protease)
  • Subtypes of HIV:
    • HIV-1:
      • Most common species worldwide
      • Similar to the simian immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview in chimpanzees
      • 4 distinct subgroups (M, N, O, and P)
      • Subgroup M: 90% of HIV/AIDS (acquired immunodeficiency syndrome) worldwide
    • HIV-2:
      • Lower infectivity, less virulent, largely confined to West Africa 
      • Similar to simian immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview from sooty mangabey monkeys
      • 8 known subgroups (A to H)
  • Transmission through bodily fluids (i.e., blood, semen, vaginal secretions, and breast milk)
Hiv virion

Diagram of the HIV virion featuring the structure of its genome and its main enzymes and glycoproteins (gp120 and gp41)

Image: “Diagram of the HIV virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview” by US National Institute of Health. License: Public Domain

Modes of HIV transmission

Sexual:

  • Unprotected sex: 
    • Responsible for 80% of infections
    • Unprotected receptive anal intercourse (URAI) in men and women > unprotected receptive vaginal intercourse
  • In anal intercourse, infection occurs:
    • With direct inoculation into the blood in the presence of traumatic tears
    • With easy access to target cells beneath the fragile rectal mucosal membrane
  • In the United States, risk noted:
    • In men who have sex with men (highest)
    • Heterosexual individuals
  • In Africa, reported infections are predominantly via heterosexual transmission (limited data on homosexual transmission rates).

Parenteral:

  • Intravenous (IV) drug use and sharing needles 
  • Accidental needle punctures in medical professionals

Vertical:

  • Mother to child during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, delivery, or breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
  • Most cases occur during delivery.
  • Risk factors for vertical transmission:
    • No antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs or prophylaxis
    • Elevated maternal viral load
    • Rupture of membranes > 4 hours

Factors affecting transmission

  • Viral load: 
    • Quantity of HIV is the primary factor determining transmission.
    • Transmission unlikely if with suppressed viral load (defined as having a viral load of < 400 HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure copies/mL)
  • Type of sexual contact: 
    • Receptive anal sex is the most high risk.
    • Circumcision reduces the risk of transmission.
  • Mucosal damage: Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, tears, sexually transmitted infection Sexually Transmitted Infection Sexually transmitted infections (STIs) are infections that spread either by vaginal intercourse, anal sex, or oral sex. Symptoms and signs may include vaginal discharge, penile discharge, dysuria, skin lesions (e.g., warts, ulcers) on or around the genitals, and pelvic pain. Some infections can lead to infertility and chronic debilitating disease. Overview: Sexually Transmitted Infections, and irritation of the genital mucous membranes increase transmission risk.
  • Recent HIV infection: elevated risk of transmission due to high viral load

Pathophysiology

HIV replication cycle

  • Target cells: CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, macrophages, and dendritic cells
  • HIV cell entry: 
    • The virion first enters via a break in a mucous membrane. 
    • The virion then crosses the mucosal barrier and seeks target cells.
  • HIV replication:
    1. Membrane fusion and binding of receptors (entry): the virion (carrying viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure, reverse transcriptase, integrase, and other proteins) initiates entry into the host cell. 
      • Virion binds the CD4 receptor and a chemokine receptor (CCR5 on macrophages, CXCR4 on T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells). 
        • Macrophage-tropic viruses: R5 strains
        • T cell-tropic viruses: X4 strains
      • Binding of gp120 with CD4 and the chemokine receptors leads to a conformational change, exposing the fusion domain at gp41.
      • This process pulls the viral and cellular membranes together, fusing them. 
    2. The capsid protein shell (surrounding the viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure and proteins) is uncoated as the virion traverses the cytoplasm.
    3. Reverse transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription: Reverse transcriptase-mediated synthesis of proviral deoxyribonucleic acid ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure) (from the viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure) occurs.
    4. Integration: Viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is transported across the nucleus and integrated into the host DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, facilitated by integrase. 
    5. Replication: Viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is transcribed, and multiple copies of new HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure form and are transported to the cytoplasm. 
      • New HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure becomes the genome of a new virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview
      • Other copies of the RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure are used to make new HIV proteins.
    6. Assembly: New viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure + proteins + enzymes move to the cell surface and form a noninfectious particle.
    7. Budding and maturation: 
      • Particle (viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure + proteins) eventually buds out of the host cell with the immature HIV.
      • Viral protein protease then cleaves newly synthesized polyproteins, producing a mature HIV.
Hiv replication cycle

HIV replication cycle:
1. Virion binds the CD4 receptor and a chemokine receptor, followed by a conformational change that facilitates fusion of the virion and the host cell.
2. A capsid protein shell (surrounding the viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure and proteins) is uncoated as the virion traverses the cytoplasm.
3. Reverse transcriptase-mediated synthesis of proviral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure occurs.
4. Viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is transported across the nucleus and integrated into the host DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, facilitated by integrase.
5. Viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is transcribed, and multiple copies of new HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure form and are transported to the cytoplasm. New HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure becomes the genome of a new virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview. Cytokine activation of the cell also occurs.
6. New viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure + proteins + enzymes move to the cell surface and form a noninfectious particle.
7. Particle (viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure + proteins) eventually buds out of the host cell with the immature HIV. Viral protein protease (enzyme) then cleaves newly synthesized polyproteins producing a mature HIV.

Image by Lecturio.
Mechanism of hiv entry and membrane fusion

Mechanism of HIV entry and membrane fusion:
1. Gp120 HIV interacts with CD4 (host cell).
2. A secondary interaction with another receptor CCR5 follows, with a conformational change in gp120.
3. The tips of gp41 are inserted into the cellular membrane.
4. Gp41 folds in half and forms coiled coils. The viral and cellular membranes pull together, leading to fusion.

Image by Lecturio.

Natural history

Acute phase (infection, dissemination, retroviral syndrome):

  • HIV infects and destroys CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, macrophages, and dendritic cells in mucosal tissues.
  • Dissemination and replication in lymph nodes occur, then proceed to other lymphoid compartments (more CD4+ target cells) → viremia
  • Further spread to the plasma and other organs follows. 
  • Antiviral immune response leads to seroconversion (about 3–7 weeks).
  • CD8+ cytolytic T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells (CTLs) are activated, and this immune response produces a partial control of viral replication.
  • Acute retroviral syndrome:
    • Clinical presentation of self-limited acute viral illness
    • Associated with millions of copies of HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure/mL of plasma
    • High likelihood of transmission during this period

Chronic phase/clinical latency:

  • Low-level replication of virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview in lymphoid tissues and slow progressive T cell depletion
  • Sustained replication generates mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, contributing to viral escape from the control of CD8+ CTLs.
  • Virus may evolve and undergo coreceptor switch (instead of 1 coreceptor, virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview can rely on either CCR5 or CXCR4).

AIDS:

  • Ongoing activation of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells results in extensive death of CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.
  • Profound immunodeficiency leads to opportunistic infections (usual cause of death).
Relationship between cd4+ t cell count and viral load

Graph of the relationship between CD4+ T cell count and viral load during the clinical course of HIV infection and AIDS:
In primary/acute infection (initial infection, dissemination, and acute retroviral syndrome), an increase in viral load (viremia) with declining CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells is noted. This period lasts weeks. In the period of clinical latency, low-level but sustained viral replication occurs and gradual decline of CD4+ cells is seen. Progression to AIDS is the result of the breakdown of host defenses, with depleted CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and increasing viral load. This process predisposes to opportunistic infections.

Image by Lecturio.

Clinical Presentation

Categories of HIV infection

The Centers for Disease Control and Prevention (CDC) classification notes that CD4+ T lymphocyte count is: 

  • A reliable indicator of disease progression
  • A guide to the clinical and therapeutic management of HIV infection
Table: 1993 revised classification system for HIV infection
CD 4+ T cell categories/stage 1 2 3
Clinical categories CD4+ ≥ 500 cells/µL CD4+ 200–499 cells/µL CD4+ < 200 cells/µL*
A: Asymptomatic, acute HIV, persistent lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy A1 A2 A3
B: Symptomatic, not A or C B1 B2 B3
C: AIDS, including opportunistic infections, neurologic disease, and tumors C1 C2 C3
* CD4 count under 200/μL is considered AIDS defining.

Clinical course and symptoms

Acute retroviral syndrome (acute phase):

  • 3–6 weeks after infection
  • Infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis-like presentation:
    • Fever, fatigue, myalgias (most common)
    • Retro-orbital headache (may have aseptic meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis), joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and rash
    • Sore throat and painful mouth sores (aphthous ulcers)
    • Hepatosplenomegaly
    • Swollen lymph nodes (mainly cervical, axillary, and occipital)
    • Nausea, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and weight loss

Chronic infection (clinical latency):

  • Few or no clinical manifestations of infection
  • Minor opportunistic infections:
    • Thrush
    • Vaginal candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
    • Herpes zoster Herpes Zoster Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Shingles (also known as herpes zoster) is more common in adults and occurs due to the reactivation of VZV. Varicella-Zoster Virus/Chickenpox
    • Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis

AIDS:

  • Without treatment, progression to AIDS takes place after a chronic phase of 7–10 years.
  • AIDS-defining diseases and malignancies
  • Opportunistic infections
  • Wasting syndrome 
  • Encephalopathy associated with HIV

AIDS

  • Defined as:
    •  CD4+ T cell count of < 200 cells/μL or a CD4+ T cell percentage of total lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes of < 14%
    • And/or at least 1 AIDS-defining condition (opportunistic infection(s) or illnesses associated with immunosuppression)
  • AIDS-defining conditions AIDS-defining conditions Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. AIDS-defining Conditions:
    • Fungal and parasitic infections:
      • Candidiasis 
      • Cryptococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
      • Cryptosporidium or Cystoisospora Cystoisospora Cystoisospora is a genus within the Coccidia subclass of protozoans. They are single-celled, obligate intracellular parasites that cause intestinal infections in humans. Humans are the only host for these species, and they are both transmitted through the fecal-oral route. The symptoms of cystoisosporiasis are watery diarrhea, abdominal pain, and fever. Cystoisospora/Cystoisosporiasis and Cyclospora/Cyclosporiasis (enteritis/ diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea)
      • Coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis
      • Pneumocystis jirovecii pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
      • Cerebral toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis 
      • Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis
    • Bacterial infections:
      • Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium avium-intracellulare
      • M. tuberculosis
      • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella septicemia
      • Nocardia Nocardia Nocardia is a branching, filamentous, gram-positive bacilli. It is partially acid fast due to the presence of mycolic acids in the cell wall. Nocardia is a ubiquitous soil organism that most commonly affects immunocompromised patients. Nocardia is transmitted via inhalation of aerosolized bacteria or less commonly, via direct contact with wounds. Nocardia/Nocardiosis
    • Viral infections:
      • Herpes zoster Herpes Zoster Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Shingles (also known as herpes zoster) is more common in adults and occurs due to the reactivation of VZV. Varicella-Zoster Virus/Chickenpox
      • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus (CMV) infections
      • Herpes simplex virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2) encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
      • Progressive multifocal leukoencephalopathy 
    • Malignancies:
      • Lymphoma (Burkitt’s, immunoblastic)
      • Kaposi’s sarcoma
      • Invasive cervical and anal carcinomas
    • Miscellaneous:
      • Wasting syndrome attributed to HIV
      • HIV-associated encephalopathy
Kaposi's sarcoma

Cutaneous lesions of Kaposi’s sarcoma

Image: “Kaposi’s sarcoma” by OpenStax College. License: CC BY 3.0

Selected infections and conditions

  • P. jiroveci pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: 
    • Risk factors:
      • CD4 count < 200/µL
      • Thrush
      • Previous Pneumocystis pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
      • Weight loss
    • Symptoms include dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and a non-productive cough.
    • Physical exam findings:
      • Tachypnea
      • Tachycardia
      • Crackles and rhonchi; normal auscultation in 50% of cases
    • Chest X-ray shows bilateral interstitial infiltrates.
    • Diagnosis: special silver staining of respiratory secretions showing classic cysts
    • Treatment:
      • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim-sulfamethoxazole
      • Alternative: clindamycin + primaquine
      • Moderate or severe hypoxemia: tapering doses of prednisone added
  • Cryptococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
    • Greatest risk if CD4 count < 100/µL
    • Symptoms include headache, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, altered mental status, and neurologic deficits.
    • Exam shows meningismus in < 40% of patients.
    • Diagnosis:
      • Lumbar puncture including measurement of opening pressure
      • Cerebrospinal fluid (CSF): ↓ white blood cell count, ↑ protein, ↓ or normal glucose 
      • CSF India ink staining (encapsulated yeast organisms), culture
      • CSF cryptococcal antigen testing
      • Serum cryptococcal antigen testing
    • Treatment:
      • Amphotericin B and flucytosine Flucytosine Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Flucytosine, Griseofulvin, and Terbinafine for 2 weeks
      • Then oral fluconazole for 8 weeks or until the patient is culture negative
  • Toxoplasma Toxoplasma Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
    • Greatest risk if CD4 count < 100/uL
    • Symptoms include headache, confusion, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and lethargy.
    • Exam shows ataxia, focal neurologic, and sensory deficits.
    • Diagnosis: 
      • Brain imaging: multiple ring-enhancing lesions
      • + Toxoplasma Toxoplasma Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis gondii IgG antibody
      • Typical clinical syndrome
    • Treatment: pyrimethamine, sulfadiazine, and folinic acid for 6 weeks
  • Disseminated M. avium complex (MAC) infection: 
    • Greatest risk if CD4 count < 50/µL
    • Symptoms include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, weight loss, night sweats, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea.
    • Exam shows lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy and hepatosplenomegaly.
    • Laboratory studies: severe anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (due to bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow involvement), ↑ alkaline phosphatase, ↑ lactate dehydrogenase
    • Diagnosis: blood cultures
    • Treatment:
      • Macrolide + ethambutol 
      • +/- Rifabutin (if with ↑ mycobacterial burden)
  • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System conditions of AIDS:
    • 90% of patients exhibit neurologic involvement on autopsy.
    • Some findings:
      • Vacuolar myelopathy: microscopically resembles subacute combined degeneration (vitamin B12 deficiency)
      • AIDS-associated peripheral neuropathies (most common: distal sensory polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy)
      • HIV meningoencephalitis: dementia, ataxia, bowel and bladder incontinence
      • AIDS dementia complex or HIV encephalopathy

Diagnosis

Diagnostic approach

  • Pre-test counseling:
    • Discuss the indication for HIV testing.
    • Risk assessment (patient risk behaviors)
    • Implications of positive test results
    • Discuss confidentiality Confidentiality Confidentiality is a set of rules that dictates the protection of health information shared by a patient with a physician. In general, this information should only be used to dictate medical decision-making steps and can only be disclosed to a 3rd party with the patient's express consent. Patient-Doctor Confidentiality and follow-up.
  • Indications for testing:
    • Screening: Test all adolescents and adults at increased risk for HIV infection, and all pregnant women.
    • Any patients with features of acute or chronic HIV infection
  • Laboratory testing:
    • 4th-generation enzyme immunoassay (EIA) for HIV-1 and -2
      • Detects antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (generally appear 3–12 weeks following infection) and p24 antigen of HIV
      • Negative result: no need for further testing
      • Positive result: Test HIV-1 and -2 antibody differentiation immunoassay.
      • Indeterminate result: Test with FDA-approved HIV-1 nucleic acid test. 
    • Other tests for HIV:  
      • Western blot: separation of viral proteins by molecular weight on polyacrylamide gel (2 bands present = positive)
      • Reverse transcriptase- polymerase chain reaction Polymerase chain reaction Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) (RT- PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)) testing: virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview quantification or HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure for monitoring
Flowchart enveloped rna viruses

Algorithm for the diagnosis and differentiation between an HIV infection produced by subtype HIV-1 and subtype HIV-2

Image by Lecturio.

Additional tests and monitoring

  • HIV-related:
    • CD4+ T cell count (assess immune function)
    • Viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure load (assess viremia)
    • HIV resistance testing or genotyping (rate of HIV resistance to current therapy: 4%–10%)
    • HLA-B*5701:
      • Obtain before starting patients on an abacavir (ABC)-containing regimen 
      • If positive, patient should not get ABC due to hypersensitivity reaction
  • HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus and HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus serology (viral hepatitis status affects choice of therapy) 
  • Other sexually transmitted diseases
  • Other tests needed for monitoring and determination of co-morbidities:
    • Basic metabolic panel
    • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests (some of the antiretrovirals cause alterations in liver function)
    • Complete blood count (CBC) with differential count
    • Fasting lipid profile (some antiretrovirals cause lipid problems)
    • Fasting glucose or hemoglobin A1c (antiretrovirals cause issues with glucose tolerance)
    • Urinalysis (due to the prevalence of HIV nephropathy)
    • Pregnancy test (treatment needed in pregnant women)
  • Monitoring:
    • Viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure load (indicator of antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs response):
      • ↓ Viral loads indicate effective treatment
      • A prognostic marker in long-term treatment
    • CD4+ T cell count: increases with antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs ( ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs)

Management

Antiretroviral drugs

  • Reverse transcriptase inhibitors interfere with the translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation of viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure:
    • Nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine, emtricitabine, tenofovir)
    • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, doravirine, etravirine)
  • Protease inhibitors (PIs):
    • Block the cleavage of protein precursors necessary for the production of infectious viral particles 
    • Examples: atazanavir, darunavir, lopinavir
  • Integrase strand transfer inhibitors 
    • Prevent the insertion of the viral genome into the host DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 
    • Examples: dolutegravir, elvitegravir
  • Entry inhibitors: 
    • CCR5 antagonist: 
      • Inhibits the attachment of the virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview to the CD4 cell by blocking binding of gp120 
      • Maraviroc
    • Fusion inhibitor: 
      • Interferes with fusion of the cell membranes of HIV and the CD4 cell 
      • Enfuvirtide
    • Attachment inhibitor: 
      • Binds gp120, preventing viral attachment 
      • Fostemsavir
    • Post-attachment inhibitor: 
      • Blocks CD4 molecule, thus inhibiting virion entry
      • Ibalizumab

Treatment approach

  • Initiate antiretroviral therapy (ART) promptly!
  • Goals:
    • Suppress plasma HIV RNA.
    • Improve immunologic function.
    • Reduce HIV-associated complications and prolong survival.
    • Prevent HIV transmission.
  • Avoiding resistance: Triple-drug therapy given HIV resistance develops quickly to 1- or 2-drug regimens.
  • Combination ART for treatment-naive patients (Department of Health and Human Services Panel, 2019):
    • Bictegravir + tenofovir alafenamide + emtricitabine 
    • Dolutegravir + tenofovir alafenamide/disoproxil fumarate + emtricitabine or lamivudine
    • Raltegravir + tenofovir alafenamide/disoproxil fumarate + emtricitabine or lamivudine 
    • Dolutegravir + abacavir + lamivudine: only for individuals who are HLA-B*5701 negative and without chronic HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus 
    • Dolutegravir + lamivudine, except for:
      • Individuals with HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure > 500,000 copies/mL
      • Individuals with HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus co-infection
      • Individuals needing to initiate ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs before the results of HIV genotypic resistance testing for reverse transcriptase or HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus testing are available
  • Once initiated, treatment is indefinite.

Immune reconstitution inflammatory syndrome (IRIS)

  • Worsening of preexisting or untreated opportunistic infections when combination antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs (cART) is initiated
    • Paradoxical IRIS: worsening of known or pre-existing condition
    • Unmasking IRIS: symptoms associated with previously undiagnosed condition
  • Frequently seen in tuberculosis
  • Onset: 1 week to a few months of cART initiation
  • Pathogenesis: inflammatory response similar to type IV hypersensitivity reaction Type IV hypersensitivity reaction Type IV hypersensitivity reaction, or delayed-type hypersensitivity, is a cell-mediated response to antigen exposure. The reaction involves T cells, not antibodies, and develops over several days. Presensitized T cells initiate the immune defense, leading to tissue damage. Type IV Hypersensitivity Reaction
  • Treatment:
    • Treat opportunistic infection.
    • May delay antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs (e.g., cryptococcal and tuberculous meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis)
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids as needed with a subsequent taper

Prevention and Prophylaxis

General prevention

  • Safe-sex practices (use of condoms)
  • Treatment of sexually transmitted diseases 
  • Male circumcision
  • Use of sterile instruments 
  • Proper personal protective equipment for medical professionals
  • Opioid substitution therapy (↓ illicit drug and injection use)
  • Adequate pre- and perinatal care (to reduce transmission to infants)
  • Pre- and post-exposure prophylaxis 
  • Adequate ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs for infected individuals

Prophylaxis

  • Post-exposure prophylaxis
    • Within 72 hours of exposure after contact with mucous membranes or parenteral contact with HIV-infected materials
    • Taken for 28 days
    • Combination of 3 antiretroviral drugs 
    • Options:
      • Raltegravir + tenofovir-emtricitabine 
      • Dolutegravir + tenofovir-emtricitabine
  • Pre-exposure prophylaxis (PrEP):
    • Reduce the risk in uninfected high-risk individuals: 
      • Sexual partners of HIV-infected patients
      • Men/transgender women who have sex with men
      • Men (who do not use condoms) in high-prevalence areas
    • Combination of emtricitabine and tenofovir
  • Perinatal prophylaxis: 
    • Highest risk of HIV transmission is during delivery.
    • Goal is to block transmission (from mother to baby): 
      • Treat HIV-positive patients immediately and do not wait for genotyping.
      • Regimen can be changed later.
    • Zidovudine or 3-drug regimen (depending on maternal viral load/risk of transmission) given to infant as prophylaxis

HIV in Special Populations

Pregnancy

  • Testing:
    • HIV testing as part of prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care
    • Repeat test in 3rd trimester in patients at high risk for HIV infection
    • Repeat test in patients with sexually transmitted disease Sexually Transmitted Disease Sexually transmitted diseases (STDs) are infections that spread either by vaginal intercourse, anal sex, or oral sex. Symptoms and signs may include vaginal discharge, penile discharge, dysuria, skin lesions (e.g., warts, ulcers) on or around the genitals, and pelvic pain. Some infections can lead to infertility and chronic debilitating disease. Overview: Sexually Transmitted Infections
  • Transmission: 
    • During pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Delivery (highest risk)
    • Breastfeeding
  • Risk depends on maternal viral load.
  • Maternal management:
    • Reducing transmission: 
      • cART throughout pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
      • Breastfeeding should be avoided in the United States (alternative infant nutrition easily available) but not in developing nations.
    • Delivery method for mothers who did not receive ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs (high risk of transmission): cesarean delivery Cesarean Delivery Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. Cesarean Delivery, if possible (based on obstetric indications)
    • Delivery methods for mothers on ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs:
      • Maternal viral load > 1,000 copies/mL (high risk of transmission): cesarean delivery Cesarean Delivery Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. Cesarean Delivery at 38 weeks (before labor Labor Labor is the normal physiologic process defined as uterine contractions resulting in dilatation and effacement of the cervix, which culminates in expulsion of the fetus and the products of conception. Normal and Abnormal Labor and rupture of membranes)
      • Maternal viral load ≤ 1,000 copies/mL but > 50 copies/mL: vaginal delivery possible (decide by obstetric indications)
      • Maternal viral load < 50 copies/mL: vaginal delivery possible (decide by obstetric indications)
    • Postpartum: Treatment should by continued by the mother.

Newborns

  • HIV diagnostic testing for all infants with perinatal HIV exposure:
    • Use PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) (HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure or HIV DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure nucleic acid tests):
      • Not HIV antibody immunoassay
      • False positives in antibody tests in children < 18 months of age (circulating maternal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins still present)
    • Timing:
      • 14–21 days
      • 1–2 months
      • 4–6 months
  • Low risk of perinatal HIV transmission:
    • Considered in:
      • Mothers on ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care with compliance
      • Confirmed HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure level of < 50 copies/mL (viral suppression) near delivery
    • Neonatal medication: zidovudine for 4 weeks
  • High risk of perinatal HIV transmission:
    • Considered in:
      • Mothers without antepartum/intrapartum ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs or only intrapartum ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs
      • Mothers without viral suppression
      • Mothers with acute HIV during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care or breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
    • Intrapartum: IV zidovudine in HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure >1000 copies/mL
    • Birth to 6 weeks (presumptive HIV therapy for neonate): 
      • Zidovudine + lamivudine + nevirapine 
      • Zidovudine + lamivudine + raltegravir
  • Presumed newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn exposure:
    • Considered in:
      • Mothers who have at least 1 positive HIV test at delivery or postpartum
      • Mothers whose newborns have a positive HIV antibody test
    • Same medications as presumptive HIV therapy for neonate
  • Newborn with HIV (confirmed HIV virologic test): Use 3-drug ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs (using appropriate doses).

Children

  • Transmission: 
    • Vertical transmission (most common route of transmission) 
    • Others: blood transfusion, sexual abuse Sexual Abuse Sexual abuse and assault are major public health problems that affect many people from all walks of life, including people of all ages and genders, but it is more prevalent in women and girls, with reports of up to 1 in 3 experiencing sexual assault at some time in their life. Sexual Abuse, injection drug use
    • Increased risk of HIV infection among those having unprotected sex, and teenage boys who have intercourse with partners of same sex
  • Presentation:
    • Children:
      • Infant rapid progressors: develop severe signs of AIDS early in life that contribute to death (by age 2–4 years)
      • Unique features: short stature, developmental delay, aspiration and swallowing problems, recurrent ear infections, and delayed puberty Delayed Puberty Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Delayed Puberty
    • Adolescents: often asymptomatic until CD4 count falls
    • Other findings:
      • Opportunistic infections
      • Organ system disease (e.g., nephropathy, encephalopathy, hepatitis)
      • Malignancy (e.g., non-Hodgkin’s lymphoma)
  • Diagnosis: 
    • < 18 months: PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) (HIV RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure or HIV DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure nucleic acid tests), not HIV antibody immunoassay
    • > 18 months: HIV antibody immunoassay
  • Management:
    • Combination antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs (3-drug regimen)
    • Treat opportunistic infections
  • Prevention:
    • Routine “opt out” testing (HIV test is included in standard preventive tests and patient is given opportunity to decline)
    • Treat pregnant women to reduce viral load (↓ transmission).
    • Infant prophylaxis
    • In United States: no breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding 
    • Routine screening offered at least by the age of 16 in high-prevalence areas
  • Immunologic categories:
    • Stages of HIV in children are dependent on age and CD4 T cell count.
    • If a stage 3 opportunistic infection is detected, the patient has AIDS regardless of level of CD4 T cell count.
Table: Centers for Disease Control and Prevention (CDC) HIV infection and AIDS stage based on age-specific CD4+ T lymphocyte count
Stage < 1 year 1–5 years ≥ 6 years
0 NA NA NA
1 ≥ 1,500 cells/µL ≥ 1,000 cells/µL ≥ 500 cells/µL
2 750–1,499 cells/µL 500–999 cells/µL 200–499 cells/µL
3 (AIDS) < 750 cells/µL < 500 cells/µL < 200 cells/µL

Elderly

  • In 2018, > 50% of HIV-infected Americans were > 50 years of age.
  • Challenges:
    • Age-related liver/kidney dysfunction may increase side effects of ART ART Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs or drug toxicity.
    • Higher risk of drug-to-drug interactions
    • Age and HIV increase the risk of cardiovascular disease, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones loss, and cancer.

Differential Diagnosis

  • Infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis (IM): a contagious viral infection caused by the Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus. Transmission is via the spread of infected saliva. Clinical manifestations include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, tonsillar pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis, and lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. The infection can be similar to acute retroviral syndrome. Diagnosis is clinical and confirmed through heterophile antibody testing. 
  • Toxoplasmosis: a disease caused by T. gondii, a parasite that lives in the feline gut (definite host). Transmission is by consumption of raw meat or food contaminated by cat feces. Presentation depends on the host’s immunity. Immunocompetent patients usually have no or mild viral symptoms. Immunocompromised patients develop cerebral or ocular toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis.
  • Cryptococcosis Cryptococcosis Cryptococcosis is an opportunistic, fungal infection caused by the Cryptococcus species. The principal pathogens in humans are C. neoformans (primary) and C. gattii. The majority of affected patients are immunocompromised. Patients with AIDS, chronic steroid use, and organ transplant are particularly affected. Cryptococcosis is an AIDS-defining illness and typically associated with CD4 count < 100 cells/μL. Cryptococcus/Cryptococcosis: a fungal infection that most often affects immunocompromised patients (e.g., AIDS, malignancy, transplant recipients, chronic corticosteroid use). Patients present with headaches and abnormal mental status. Cryptococcal capsular antigen in CSF and culture establish the diagnosis.
  • Hodgkin’s lymphoma: a malignancy of B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells within the lymph nodes. Presentation of the disease is with palpable nontender lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, mostly in the neck, supraclavicular area, and axilla Axilla The axilla is a pyramid-shaped space located between the upper thorax and the arm. The axilla has a base, an apex, and 4 walls (anterior, medial, lateral, posterior). The base of the pyramid is made up of the axillary skin. The apex is the axillary inlet, located between the 1st rib, superior border of the scapula, and clavicle. Axilla and Brachial Plexus. Constitutional “B symptoms” ( fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats, and weight loss) are also noted. The pathognomic histological finding is a Reed-Sternberg cell (giant B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells with eosinophilic inclusions).

References

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