Anti-HIV Drugs

Overview

Antiretroviral drugs

• Classified based on the phase of the retrovirus life cycle that the drug inhibits
• Goal: suppress viral replication in human immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome 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 (HIV) infection
• Standard of care Standard of care The minimum acceptable patient care, based on statutes, court decisions, policies, or professional guidelines. Malpractice: at least 3 drugs taken simultaneously

Virion structure of HIV

• Virion envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology contains 2 membrane glycoproteins Glycoproteins Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. Basics of Carbohydrates:
  • gp41 Gp41 Transmembrane envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 41, 000 and is glycosylated. The n-terminal part of gp41 is thought to be involved in cell fusion with the CD4 antigens of T4 lymphocytes, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by immunoblotting. HIV Infection and AIDS (transmembrane)
  • gp120 Gp120 External envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 120 kda and contains numerous glycosylation sites. Gp120 binds to cells expressing CD4 cell-surface antigens, most notably t4-lymphocytes and monocytes/macrophages. Gp120 has been shown to interfere with the normal function of CD4 and is at least partly responsible for the cytopathic effect of HIV. HIV Infection and AIDS (surface/docking protein)
• Matrix protein Matrix protein Proteins associated with the inner surface of the lipid bilayer of the viral envelope. These proteins have been implicated in control of viral transcription and may possibly serve as the ‘glue’ that binds the nucleocapsid to the appropriate membrane site during viral budding from the host cell. Parainfluenza Virus 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 core
• 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 core:
  • Capsid Capsid The outer protein protective shell of a virus, which protects the viral nucleic acid. Capsids are composed of repeating units (capsomers or capsomeres) of capsid proteins which when assembled together form either an icosahedral or helical shape. Virology protein p24
  • 2 single-stranded, enveloped positive-sense ribonucleic acid Ribonucleic acid A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure ( RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure) 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 Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS, integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS, protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS)

Replication cycle of HIV

• Target cells: CD4+ T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions, macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, and dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions
• HIV cell entry HIV cell entry Human Immunodeficiency Virus (HIV):
  • The virion first enters via a break in the mucous membrane Mucous membrane An epithelium with mucus-secreting cells, such as goblet cells. It forms the lining of many body cavities, such as the digestive tract, the respiratory tract, and the reproductive tract. Mucosa, rich in blood and lymph vessels, comprises an inner epithelium, a middle layer (lamina propria) of loose connective tissue, and an outer layer (muscularis mucosae) of smooth muscle cells that separates the mucosa from submucosa. Barrett Esophagus. 
  • The virion crosses the mucosal barrier and seeks target cells.
• HIV replication:
  1. Membrane fusion and binding of receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (entry): the virion (carrying viral RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure, reverse transcriptase Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS, integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS, and other proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis) initiates entry into the host cell.
     • Virion binds the CD4 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and a chemokine receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( CCR5 CCR5 Ccr receptors with specificity for chemokine ccl3; chemokine ccl4; and chemokine ccl5. They are expressed at high levels in T-lymphocytes; B-lymphocytes; macrophages; mast cells; and nk cells. The ccr5 receptor is used by the human immunodeficiency virus to infect cells. HIV Infection and AIDS on macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, CXCR4 CXCR4 Cxcr receptors with specificity for cxcl12 chemokine. The receptors may play a role in hematopoiesis regulation and can also function as coreceptors for the human immunodeficiency virus. HIV Infection and AIDS on T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions).
       • Macrophage tropic viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology: R5 strains R5 strains HIV Infection and AIDS
       • T cell tropic viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology: X4 strains X4 strains HIV Infection and AIDS
     • Binding of gp120 Gp120 External envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 120 kda and contains numerous glycosylation sites. Gp120 binds to cells expressing CD4 cell-surface antigens, most notably t4-lymphocytes and monocytes/macrophages. Gp120 has been shown to interfere with the normal function of CD4 and is at least partly responsible for the cytopathic effect of HIV. HIV Infection and AIDS with CD4 and the chemokine receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors leads to a conformational change, exposing the fusion domain at gp41 Gp41 Transmembrane envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 41, 000 and is glycosylated. The n-terminal part of gp41 is thought to be involved in cell fusion with the CD4 antigens of T4 lymphocytes, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by immunoblotting. HIV Infection and AIDS.
     • This process pulls the viral and cellular membranes together, fusing them. 
  2. The capsid Capsid The outer protein protective shell of a virus, which protects the viral nucleic acid. Capsids are composed of repeating units (capsomers or capsomeres) of capsid proteins which when assembled together form either an icosahedral or helical shape. Virology protein shell (surrounding the viral RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure and proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis) 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 Synthesis Polymerase Chain Reaction (PCR) of proviral deoxyribonucleic acid Deoxyribonucleic acid A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure or DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure (from the viral RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure) occurs.
  4. Integration: Viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is transported across the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles and integrated into the host DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, facilitated by integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS.
  5. Replication: Viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure is transcribed and multiple copies of new HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure are formed, which are transported to the cytoplasm.
     • New HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure becomes the genome Genome The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics of the 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. 
     • Other copies of the RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure are used to make new HIV proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis.
  6. Assembly: New viral RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure + proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis + 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 move to the cell surface and form noninfectious particles.
  7. Budding Budding Mycology and maturation:
     • Particles (viral RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure + proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis) eventually bud out of the host cell with the immature HIV.
     • Viral protein protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS then cleaves the newly synthesized polyproteins, producing mature HIV.

Major classes of antiretroviral drugs

Failure of an antiretroviral regimen

• Persistently elevated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure levels in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with previously undetectable 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, even with continued treatment 
• Indicates resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to 1 or more drugs in the regimen 
• Requires change in regimen (need to implement a completely new combination of drugs)

Nucleoside Reverse Transcriptase Inhibitors and Nucleotide Reverse Transcriptase Inhibitors

Drugs

• NRTIs:
  • Zidovudine (ZDV) or azidothymidine (AZT): representative NRTI
  • Lamivudine (3TC)
  • Abacavir (ABC)
  • Emtricitabine (FTC)
  • Entecavir (ETV)
  • Truvada (emtricitabine/tenofovir)
  • Zalcitabine (ddC): discontinued
• NtRTI (tenofovir, the only nucleotide analog):
  • Tenofovir alafenamide (TAF) 
  • Tenofovir disoproxil fumarate Fumarate Citric Acid Cycle (TDF)
• NRTIs no longer recommended for use (United States Department of Health and Human Services ( HHS HHS Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises), 2019):
  • Didanosine (ddI): lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
  • Stavudine (d4T): lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis

Mechanism of action

• Act as chain terminators of the proviral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure (lack 3′-hydroxy group, so other nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids cannot continue attaching)
• Competitively bind BIND Hyperbilirubinemia of the Newborn to the deoxynucleotide triphosphate (dNTP)-binding site of reverse transcriptase Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS, terminating elongation Elongation Polymerase Chain Reaction (PCR)

Side effects

• Mitochondrial toxicity Toxicity Dosage Calculation:
  • Intracellular triphosphates for NRTIs do not affect human DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase α and polymerase β. 
  • Some intracellular triphosphates for NRTIs inhibit human DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase γ (mitochondrial enzyme), resulting in toxicities related to the inhibition of mitochondrial DNA Mitochondrial DNA Double-stranded DNA of mitochondria. In eukaryotes, the mitochondrial genome is circular and codes for ribosomal rnas, transfer rnas, and about 10 proteins. DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR).
  • Seen as:
    • Lipodystrophy: abnormal distribution of fat, “buffalo hump”
    • Hepatic steatosis Steatosis Nonalcoholic Fatty Liver Disease
    • Peripheral neuropathy Neuropathy Leprosy
    • Pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
    • Lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Didanosine, stavudine: ↑ risk of mitochondrial toxicity Toxicity Dosage Calculation
  • Phosphorylated emtricitabine, lamivudine, and tenofovir do not affect human DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase γ (no mitochondrial toxicity Toxicity Dosage Calculation).
• Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms: 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 and Types, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
• Gastrointestinal (GI): nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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, acute cholestatic hepatitis Cholestatic Hepatitis Drug-Induced Liver Injury
• Agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, headaches, myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy, and insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia

Important features

• NRTIs: for HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS and HIV-2 HIV-2 An HIV species related to HIV-1 but carrying different antigenic components and with differing nucleic acid composition. It shares serologic reactivity and sequence homology with the simian lentivirus simian immunodeficiency virus and infects only t4-lymphocytes expressing the CD4 phenotypic marker. HIV Infection and AIDS infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• NRTIs are prodrugs: should be triphosphorylated to be active
• NtRTI (tenofovir): should be diphosphorylated to be active
• Metabolism and elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy:
  • Tenofovir: long elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics (17 hours)
  • Emtricitabine, lamivudine, tenofovir: renal excretion of parent drug
  • Zidovudine, abacavir: hepatic (glucuronidation)
• Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing: rapid, especially when used as single agent

Summary of NRTI and NtRTI drugs

Non-nucleoside Reverse Transcriptase Inhibitors

Drugs

• 1st generation:
  • Efavirenz (EFV)
  • Nevirapine (NVP): not for initial treatment of HIV
• 2nd generation:
  • Etravirine (ETV)
  • Rilpivirine (RPV)
  • Doravirine (DOR)
• Delavirdine (DLV): no longer recommended for use (United States HHS HHS Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises, 2019)

Mechanism of action

Non-competitive inhibitors of reverse transcriptase Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS: 

• Bind BIND Hyperbilirubinemia of the Newborn directly to reverse transcriptase Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS and inhibit viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
• Induce conformational changes in the enzyme structure, making it inactive

Side effects

• Rash Rash Rocky Mountain Spotted Fever, GI symptoms, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, 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
• Hepatotoxicity Hepatotoxicity Acetaminophen (increase in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy 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)

Important features

• For HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS infection
• No effect on host-cell DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase
• Metabolism: hepatic (by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (CYP))
• Concomitant use of potent CYP inducers or inhibitors should be avoided.
• Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
  • Drug-resistance rate: 2%–8%
  • 1st-generation drugs have different resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing profiles than 2nd-generation drugs.
  • Do not use as monotherapy; should be combined with other agents to avoid resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing.

Summary of NNRTI drugs

Protease Inhibitors

Drugs

• Darunavir (DRV)
• Atazanavir (ATV)
• Ritonavir (RTV)
• Lopinavir (LPV): not for initial treatment of HIV
• Fosamprenavir (FPV): not for initial treatment of HIV
• Tipranavir (TPV): not for initial treatment of HIV
• No longer recommended for use (United States HHS HHS Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises, 2019):
  • Indinavir (IDV)
  • Nelfinavir (NFV)
  • Saquinavir (SQV): discontinued in the United States

Mechanism of action

• Attachment to HIV aspartyl protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS enzyme, preventing cleavage of Gag-Pol polyproteins and making the newly created virions immature/non-infectious
• Boosting protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS inhibitors (PIs):
  • Goal: inhibit metabolic clearance of HIV PIs (to improve oral bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics and prolong elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics)
  • Medications/boosting agents used:
    • Ritonavir
    • Cobicistat (a ritonavir analog): better tolerated 
  • Effects:
    • Allows for reduction in drug dose and dosing frequency 
    • Increases drug concentration

Side effects

• GI symptoms: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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
• Dyslipidemias Dyslipidemias Abnormalities in the serum levels of lipids, including overproduction or deficiency. Abnormal serum lipid profiles may include high total cholesterol, high triglycerides, low high density lipoprotein cholesterol, and elevated low density lipoprotein cholesterol. Lipid Disorders, fat deposition, or metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome
• Lipodystrophy
• Hepatotoxicity Hepatotoxicity Acetaminophen
• Hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus, diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis
• Bleeding in hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia
• PR prolongation

Important features

• Active against:
  • HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS and HIV-2 HIV-2 An HIV species related to HIV-1 but carrying different antigenic components and with differing nucleic acid composition. It shares serologic reactivity and sequence homology with the simian lentivirus simian immunodeficiency virus and infects only t4-lymphocytes expressing the CD4 phenotypic marker. HIV Infection and AIDS
  • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). 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 can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus 
• Metabolism:
  • Extensively metabolized by CYP 3A4 (except nelfinavir: CYP 2C19)
  • Concomitant administration of other potent CYP inducers or inhibitors should be avoided.
• Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing uncommon

Summary of protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS inhibitors

Integrase Strand Transfer Inhibitors

Drugs

• Raltegravir (RAL)
• Elvitegravir (EVG)
• Dolutegravir (DTG)
• Bictegravir (BIC)

Mechanism of action

• Binds to viral integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS enzyme, responsible for integration of viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure into host DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure of the infected cell 
• Inhibits binding of the preintegration complex

Side effects

• Usually well tolerated
• Weight gain
• GI symptoms, dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome), fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
• Increases creatine kinase Creatine kinase A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: the mm type from skeletal muscle, the mb type from myocardial tissue and the bb type from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. Skeletal Muscle Contraction (potential myopathy Myopathy Dermatomyositis or rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis)
• Depression (suicidal ideations)

Important features

• Effective against both HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS and HIV-2 HIV-2 An HIV species related to HIV-1 but carrying different antigenic components and with differing nucleic acid composition. It shares serologic reactivity and sequence homology with the simian lentivirus simian immunodeficiency virus and infects only t4-lymphocytes expressing the CD4 phenotypic marker. HIV Infection and AIDS
• Considered preferred 3rd agent for treatment-naïve patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Neutral effect on lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids; option for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with coronary artery disease Coronary artery disease Pathological processes of coronary arteries that may derive from a congenital abnormality, atherosclerotic, or non-atherosclerotic cause. Stable and Unstable Angina
• Metabolism:
  • Raltegravir and dolutegravir: glucuronidation
  • Bictegravir: cleared by glucuronidation and CYP
  • Elvitegravir: formulated with cobicistat (which is metabolized by CYP); thus, associated with ↑ drug-drug interactions 
• Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to raltegravir or elvitegravir increases risk of integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing.
• Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing uncommon with dolutegravir, bictegravir

Summary of integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS strand transfer inhibitors

Entry Inhibitors and Post-attachment Inhibitor

Entry inhibitors

• CCR5 CCR5 Ccr receptors with specificity for chemokine ccl3; chemokine ccl4; and chemokine ccl5. They are expressed at high levels in T-lymphocytes; B-lymphocytes; macrophages; mast cells; and nk cells. The ccr5 receptor is used by the human immunodeficiency virus to infect cells. HIV Infection and AIDS antagonist: maraviroc (MVC)
  • Mechanism of action: blocks CCR5 CCR5 Ccr receptors with specificity for chemokine ccl3; chemokine ccl4; and chemokine ccl5. They are expressed at high levels in T-lymphocytes; B-lymphocytes; macrophages; mast cells; and nk cells. The ccr5 receptor is used by the human immunodeficiency virus to infect cells. HIV Infection and AIDS coreceptor, interfering with HIV entry
  • Side effects:
    • Hepatotoxicity Hepatotoxicity Acetaminophen
    • Rash Rash Rocky Mountain Spotted Fever or systemic allergic reactions Allergic Reactions Type I hypersensitivity reaction against plasma proteins in donor blood Transfusion Reactions
    • Cough, upper respiratory infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Joint pains
  • Important features:
    • For predominantly CCR5-tropic 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 ( HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS)
    • Metabolism: renal and hepatic
    • In all regimens where maraviroc is combined with other antiretrovirals, dose adjustment is needed.
    • When combined with CYP3A inhibitors → maraviroc dose is lower; with CYP3A inducers → maraviroc dose is higher
    • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing develops when coreceptor switch occurs (shift in tropism).
• Fusion inhibitor: enfuvirtide (INN)
  • Mechanism of action: binds gp41 Gp41 Transmembrane envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 41, 000 and is glycosylated. The n-terminal part of gp41 is thought to be involved in cell fusion with the CD4 antigens of T4 lymphocytes, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by immunoblotting. HIV Infection and AIDS of HIV, preventing fusion with CD4 T cell
  • Side effects: 
    • Complications at the injection site ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion, induration Induration Dermatologic Examination, and nodules)
    • Increased incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of 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 
  • Important features: 
    • For HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS infection
    • Administered as subcutaneous injection
    • Does not inhibit CYP or affect CYP substrates
• Attachment inhibitor: fostemsavir (FTR)
  • Mechanism of action: 
    • Fostemsavir: a prodrug Prodrug Nitroimidazoles that is converted to temsavir
    • Temsavir binds gp120 Gp120 External envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 120 kda and contains numerous glycosylation sites. Gp120 binds to cells expressing CD4 cell-surface antigens, most notably t4-lymphocytes and monocytes/macrophages. Gp120 has been shown to interfere with the normal function of CD4 and is at least partly responsible for the cytopathic effect of HIV. HIV Infection and AIDS, inhibiting virion attachment to the host T cell.
  • Side effects:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • QT prolongation
    • Can increase liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy 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 in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus/C
  • Important features:
    • For HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS infection
    • Potent CYP3A inducer that decreases drug levels

Post-attachment inhibitor

• Drug: ibalizumab
• Mechanism of action:
  • Monoclonal antibody
  • Binds CD4 molecule and blocks virion entry
• Side effects:
  • Rash Rash Rocky Mountain Spotted Fever
  • GI symptoms
  • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Increased creatinine
• Important features:
  • For HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS infection
  • For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with multidrug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
  • Administered intravenously (after initial dose, given every 14 days)

Combined Antiretroviral Therapy (cART) Regimens

Antiretroviral guidelines for adults and adolescents ( HHS HHS Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Hyperglycemic Crises, 2019)

• Antiretroviral therapy (ART) recommended to:
  • Reduce morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status and mortality Mortality All deaths reported in a given population. Measures of Health Status
  • Reduce HIV transmission
• ART must be initiated immediately after the diagnosis of HIV.
• Recommended initial regimens:
  • Bictegravir + tenofovir alafenamide + emtricitabine 
  • Dolutegravir + tenofovir alafenamide/disoproxil fumarate Fumarate Citric Acid Cycle + emtricitabine or lamivudine
  • Raltegravir + tenofovir alafenamide/disoproxil fumarate Fumarate Citric Acid Cycle + emtricitabine or lamivudine 
• Initial regimens that have to meet certain criteria:
  • Dolutegravir + abacavir + lamivudine: only for individuals who are HLA-B HLA-B Class I human histocompatibility (HLA) surface antigens encoded by more than 30 detectable alleles on locus B of the HLA complex, the most polymorphic of all the HLA specificities. Several of these antigens (e.g., hla-b27, -b7, -b8) are strongly associated with predisposition to rheumatoid and other autoimmune disorders. Like other class I HLA determinants, they are involved in the cellular immune reactivity of cytolytic T lymphocytes. Organ Transplantation*5701 negative and without chronic hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus 
  • Dolutegravir + lamivudine, except for:
    • Individuals with HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure > 500,000 copies/mL
    • Individuals with hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus 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 ( 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 in whom ART should be initiated before obtaining results of HIV genotypic resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing testing for reverse transcriptase Reverse transcriptase A reverse transcriptase encoded by the pol gene of HIV. It is a heterodimer of 66 kda and 51 kda subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse h activity that plays an essential role the viral replication process. HIV Infection and AIDS 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

Antiretroviral management of pregnant women

• Treatment-naïve pregnant women are recommended ART.
• Drug regimen consists of:
  • Dual NRTI backbone
  • 3rd drug (either integrase Integrase Enzyme of the human immunodeficiency virus that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Infection and AIDS inhibitor or protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS inhibitor)
• Regimen:
  • NRTI backbone options:
    • Abacavir + lamivudine (Abacavir should not be used in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship positive for HLA-B HLA-B Class I human histocompatibility (HLA) surface antigens encoded by more than 30 detectable alleles on locus B of the HLA complex, the most polymorphic of all the HLA specificities. Several of these antigens (e.g., hla-b27, -b7, -b8) are strongly associated with predisposition to rheumatoid and other autoimmune disorders. Like other class I HLA determinants, they are involved in the cellular immune reactivity of cytolytic T lymphocytes. Organ Transplantation*5701; not recommended if pretreatment HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure is > 100,000 copies/mL)
    • Tenofovir disoproxil fumarate Fumarate Citric Acid Cycle + emtricitabine
    • Tenofovir disoproxil fumarate Fumarate Citric Acid Cycle + lamivudine
  • 3rd drug options:
    • Dolutegravir (small risk of neural-tube defects)
    • Raltegravir
    • Atazanavir + ritonavir (risk of maternal hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice)
    • Darunavir + ritonavir

Antiretroviral management of newborns

• Low risk of perinatal HIV transmission:
  • Considered in:
    • Mothers on ART during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, who are compliant
    • Confirmed HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure level of < 50 copies/mL (viral suppression Suppression Defense Mechanisms) near delivery
  • Neonatal medication: zidovudine for 4 weeks
• High risk of perinatal HIV transmission:
  • Considered in:
    • Mothers without antepartum/intrapartum ART or only intrapartum ART
    • Mothers without viral suppression Suppression Defense Mechanisms
    • Mothers with acute HIV during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and 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: intravenous zidovudine if HIV RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure > 1,000 copies/mL
  • Birth up to 6 weeks (presumptive HIV therapy for neonates):
    • Zidovudine + lamivudine + nevirapine 
    • Zidovudine + lamivudine + raltegravir
• Presumed newborn Newborn An infant during the first 28 days after birth. 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 as presumptive HIV therapy for neonates
• Newborns with HIV (confirmed HIV virologic test): use 3-drug ART (using appropriate doses)