Antivirals for Hepatitis C

Antivirals against hepatitis C include a wide range of drug classes. The previous treatment regimen included interferon alfa (IFN-α) and ribavirin, which target viral entry, immune modulation, and viral replication. New, direct-acting antiviral (DAV) agents target specific nonstructural (NS) proteins of hepatitis C virus Hepatitis C Virus 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 ( 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), which are important for viral replication. These agents include NS3A/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors. DAVs are often given in combination therapy and are the preferred management of hepatitis C due to their high success rate and milder side effect profile.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

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 virus ( 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)

  • 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 
  • Family: Flaviviridae
  • Transmitted via: 
    • Parenteral
      • Blood and blood products
      • Intravenous drug use
    • Perinatal
    • Sexual intercourse
  • Infection can lead to: 
    • Acute and chronic hepatitis
    • Cirrhosis
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)

Viral proteins

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 virus 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 encodes:

  • 3 structural proteins: 
    • Core (contains 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)
    • Envelope 1 and envelope 2 (on the lipid envelope)
  • 6 nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B)
    • Important for viral replication 
    • Targets of the newer antiviral agents
Hcv genome

Viral structure of hepatitis C and the proteins that are translated from its genome:
Structural proteins include core, envelope 1 (E1), and E2. NS2, NS3, NS4A, NS4B, NS5A, and NS5B are nonstructural (NS) proteins, most of which are the targets for direct-acting antiviral therapy.

Image: “ 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 genome” by Mostafa H. Elberry, Noureldien H. E. Darwish, and Shaker A. Mousa. License: CC BY 4.0

Treatment regimens

  • Acute infection: interferon alfa (IFN-α)
  • Chronic infection:
    • Depends on the genotype
    • Previously used treatments: 
      • IFN-α
      • Ribavirin
    • Now replaced with direct-acting antivirals (DAVs):
      • NS3/4A protease inhibitors 
      • NS5A inhibitors
      • NS5B 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 polymerase inhibitors 
    • Direct-acting antivirals are typically given as a combination therapy. 
      • > 90% success rate 
      • No significant side effects

IFN-α

Chemistry

Interferons Interferons Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons are a type of signaling protein belonging to the cytokines family.

Mechanism of action

IFN-α works through several mechanisms:

  • Induces intracellular signals responsible for inhibition of viral:
    • Entry into a cell
    • Protein processing
    • Replication
  • Modulates the immune system:
    • ↑ Expression of MHC molecules
    • ↑ Phagocytic activity
    • ↑ Survival, proliferation, and activity of cytotoxic CD8+ 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 natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes → lysis of infected cells

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
    • Available in IV, IM, and SC forms
    • Poor oral bioavailability 
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption is slow.
  • Metabolism: undergoes proteolysis by endogenous proteases 
  • Excretion: renal and biliary

Indications

  • Hepatitis:
    • 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 
    • 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
      • Acute
      • Chronic (in combination with ribavirin)
    • Chronic hepatitis D Hepatitis D Hepatitis D is caused by HDV, a small enveloped, single-stranded RNA virus. HBV is a satellite virus, as it requires the presence of hepatitis B virus (HBV) for assembly and secretion. Therefore, in order for an individual to contract hepatitis D, coinfection or superinfection with HBV is required. Clinical presentation is that of a classical viral hepatitis, including coinfection of HDV and HBV. Hepatitis D Virus
    • Chronic hepatitis E Hepatitis E The hepatitis E virus (HEV) is a small nonenveloped virus that contains linear, single-stranded, positive-sense RNA, making it similar to norovirus. Transmission of HEV is via the fecal-oral route and is clinically similar to that of hepatitis A. However, unlike hepatitis A, hepatitis E is quite severe, especially in pregnant women, and may cause fulminant hepatitis. Hepatitis E Virus
  • Malignancies, such as:
    • Non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma (NHL)
    • Malignant melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
    • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia ( HCL HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia)
    • Kaposi sarcoma 
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (MM)
  • Other hematologic conditions:
    • Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera (PCV)
    • Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura (TTP)

Adverse effects

  • Flu-like syndrome
    • Headache
    • Fever and chills
    • Myalgia
    • Malaise
  • Transient ↑ 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 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 after 8–10 weeks of therapy
  • On prolonged therapy:
    • CNS effects
      • Mood disorders
      • 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
      • Confusion
      • Suicidal thoughts 
    • Bone marrow suppression
      • 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
    • Induction of autoantibodies and autoimmune disease

Contraindications

  • Decompensated 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 disease
  • Autoimmune diseases
  • Prior history of cardiac arrhythmia
  • Uncontrolled seizure disorder
  • 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

Drug interactions

  • ↑ Serum levels of:
    • Methadone
    • Theophylline
  • ↑ Risk of 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 failure → didanosine 
  • ↑ Risk of myelosuppression with:
    • Zidovudine
    • Clozapine

Ribavirin

Chemistry

  • Guanosine analogue
  • Prodrug → metabolized into active form within cells

Mechanism of action

  • Resembles guanosine → interferes with the synthesis of guanosine triphosphate (GTP) 
  • Inhibits 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-dependent polymerase of some viruses
  • Results in inhibition of:
    • Viral replication ( 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 and 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)
    • Viral protein synthesis

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Rapidly absorbed
    • Bioavailability:
      • ↑ With high-fat meals
      • ↓ With antacids
  • Distribution:
    • Large volume of distribution
    • Not protein bound
  • Metabolism: phosphorylated intracellularly to active metabolites
  • Excretion: 
    • Urine (primary)
    • Feces

Indications

  • Viral hepatitis:
    • Chronic hepatitis C (in combination with IFN)
    • Chronic hepatitis E Hepatitis E The hepatitis E virus (HEV) is a small nonenveloped virus that contains linear, single-stranded, positive-sense RNA, making it similar to norovirus. Transmission of HEV is via the fecal-oral route and is clinically similar to that of hepatitis A. However, unlike hepatitis A, hepatitis E is quite severe, especially in pregnant women, and may cause fulminant hepatitis. Hepatitis E Virus 
  • Respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus ( RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus) infection 
  • Specific viral hemorrhagic fevers (such as Lassa 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)

Adverse effects

  • Pruritis
  • GI upset
  • Depression
  • Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia (HA) (dose dependent)

Contraindications

  • 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
  • Significant cardiovascular disease (potential severe anemia → myocardial ischemia)
  • Severe renal impairment
  • 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 (teratogenic)

Drug interactions

  • ↑ Risk of mitochondrial toxicity: didanosine
  • Myelosuppression
    • Azathioprine
    • Zidovudine (particularly anemia)

NS3A/4A Protease Inhibitors

Medications in this class

  • Simeprevir
  • Glecaprevir
  • Grazoprevir
  • Paritaprevir
  • Voxilaprevir

Mechanism of action

NS3A/4A protease inhibitors is a drug class that inhibits NS3/4A serine protease, which is necessary for 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 replication.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Distribution: protein-bound
  • Metabolized: cytochrome P450 (CYP) 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 (mainly CYP3A)
  • Excretion: mainly in feces

Indications

NS3A/4A protease inhibitors are used (usually in combination therapy with another DAV) to treat chronic hepatitis C.

Adverse effects

  • Nausea
  • Headache
  • Fatigue
  • 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
  • Rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes and photosensitivity

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • CYP3A4 inducers and inhibitors → alter levels of NS3A/4A protease inhibitors

NS5A Inhibitors

Medications in this class

  • Daclatasvir
  • Ledipasvir
  • Velpatasvir
  • Elbasvir
  • Ombitasvir
  • Pibrentasvir

Mechanism of action

  • The exact mechanism is unclear.
  • Bind to NS5A → inhibit viral replication

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: generally well absorbed
  • Distribution: protein bound
  • Metabolism: Most are metabolized by the CYP system (often CYP3A4).
  • Elimination: mainly in feces

Indications

These medications are used (usually in combination therapy with another DAV) for the treatment of chronic hepatitis C.

Adverse effects

  • Headache
  • Fatigue 
  • Nausea

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • CYP3A4 inducers and inhibitors → alter levels of NS5A inhibitors

NS5B RNA-Dependent RNA Polymerase Inhibitors

Classification

  • Nucleoside/nucleotide polymerase inhibitors (NPIs): sofosbuvir
  • Non-nucleoside polymerase inhibitors (NNPIs): dasabuvir

Mechanism of action

NS5B 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-dependent 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 polymerase inhibitors target NS5B (an 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-dependent 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 polymerase).

  • NPIs are activated in hepatocytes → compete with nucleotides and incorporated into 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 → new nucleotides cannot be added → viral replication halts
  • NNPIs allosterically bind to NS5B → ↓ polymerase function → inhibit viral replication

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Distribution: protein bound
  • Metabolism: 
    • NPIs phosphorylated in hepatocytes → active form
    • Dasabuvir: CYP2C8 and CYP3A
  • Excretion:
    • Sofosbuvir: primarily urine
    • Dasabuvir: primarily feces

Indications

NS5B 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-dependent 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 polymerase inhibitors are used (usually in combination therapy with another DAV) for the treatment of chronic hepatitis C.

Adverse effects

  • Fatigue
  • Headache
  • 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
  • Nausea
  • May reactivate 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

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • Amiodarone → ↑ bradycardia (with sofosbuvir)

References

  1. Miller, K. (n.d.) Hepatitis C treatments. WebMD, https://www.webmd.com/hepatitis/understanding-hepatitis-c-treatment
  2. Centers for Disease Control and Prevention. (n.d). Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. CDC. Retrieved February 10, 2021, from https://www.cdc.gov/hepatitis/hcv/management.htm
  3. Hepatitis C Online. (n.d.) HCV medications. https://www.hepatitisc.uw.edu/page/treatment/drugs
  4. Chopra, S, & Pockros, P. (2020). Overview of the management of chronic hepatitis C virus infection. UpToDate. Retrieved January 28, 2021, from https://www.uptodate.com/contents/overview-of-the-management-of-chronic-hepatitis-c-virus-infection
  5. Pockros, PJ. (2021). Direct-acting antivirals for the treatment of hepatitis C virus infection. In Bloom, A. (Ed.), UpToDate. Retrieved August 5, 2021, from https://www.uptodate.com/contents/direct-acting-antivirals-for-the-treatment-of-hepatitis-c-virus-infection#H1225365836
  6. Ahmed, A, & Daniel JF. Mechanisms of hepatitis C viral resistance to direct-acting antivirals. Viruses, Vol. 7, No. 12, Dec. 2015, pp. 6716–29.
  7. HCV Guidelines. (n.d.) Simplified HCV treatment* for treatment-naive adults without cirrhosis. HCV Guidelines. https://www.hcvguidelines.org/treatment-naive/simplified-treatment
  8. Thomas, H, Foster, G, & Platis, D. (2003). Mechanisms of action of interferon and nucleoside analogues. Journal of Hepatology. 39:S93-S98. https://www.journal-of-hepatology.eu/article/S0168-8278(03)00207-1/pdf
  9. Safrin, S. (2012). Antiviral agents. In Katzung, BG, Masters, SB, & Trevor, AJ. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 861–890). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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