Hepatitis C

guideline review,management protocol,Scientific discussion of hepatitis C

1. Hepatitis C Presenter: Dr.Melaku Y.(IMR3) Moderator: Dr.Geda Lelisa (Internist, Gastroenterologist and Hepatologist) May,2022

2. Outline Introduction Virology Epidemiology Pathogenesis Clinical Features Diagnosis Liver biopsy and Non-invasive assessment of fibrosis Natural History Treatment 5/19/2022 2

3. Introduction More than 71 million people worldwide are chronically infected with HCV (WHO,2015) 399 000 Deaths from cirrhosis or hepatocellular carcinoma caused by HCV infection. HCV successfully evades the host immune response in 50% to 90% of acutely infected persons Complications of HCV-related cirrhosis remain a leading indication for LT in the USA and Europe. 5/19/2022 3

4. Introduction 5/19/2022 4 N Engl J Med 2019;380:2041-50

5. Introduction 5/19/2022 5 N Engl J Med 2019;380:2041-50

6. Virology Structure: The HCV virion is an enveloped virus that is 50 nm in diameter The 2 envelope proteins, E1 and E2, heterodimerize and assemble into tetramers icosahedral symmetry The envelope proteins are anchored to a host cell–derived lipid bilayer envelope membrane The nucleocapsid is believed to be composed of multiple copies of the core protein and forms an internal icosahedral viral coat 5/19/2022 6

7. 5/19/2022 7

8. Virology… Genomic organization: HCV is a single-stranded positive-sense RNA virus that belongs to the Flaviviridae family member of the genus Hepacivirus The genome of HCV contains approximately 9600 nucleotides with an open reading frame (ORF) The HCV ORF is flanked upstream by a 5′ untranslated region (UTR) that functions as an internal ribosome entry site and by a 3′ UTR that is critical for initiation of new RNA strand synthesis. The 5′ and portions of the 3′ UTR are the most conserved regions of the HCV genome.  5/19/2022 8

9. Virology… Viral Replication and Life Cycle: HCV entry involves the attachment of envelope proteins E1 and E2 to cell surface molecules The expression and function of CD81 and human scavenger receptor are essential for HCV entry into hepatocytes Once HCV attaches to the cell, endocytosis of the bound virion is presumed to occur A pH drop in the vesicle causes conformational changes in the glycoproteins. 5/19/2022 9

10. Virology… Viral Replication and Life Cycle: 11 viral proteins, including both structural and nonstructural proteins HCV replication is catalyzed by the NS5B RNA-dependent RNA polymerase (RdRp) The positive-strand genomic RNA serves as a template for the synthesis of a negative-strand intermediate The negative-strand RNA serves as a template for production of numerous strands of RNA of positive polarity 5/19/2022 10

11. Virology… 5/19/2022 11

12. 5/19/2022 12

13. 5/19/2022 13

14. Virology… Viral Protein Function: E1 and E2 proteins: Form highly glycosylated heterodimers and then tetramers that are essential for viral assembly. Mediate cell entry by binding to surface receptors. Responsible for fusion between the host cell membrane and the viral envelope. They are targets of host antibodies. The first 27 amino acids of E2 form hypervariable region 1 (HVR1) 5/19/2022 14

15. Virology… Viral Protein Function: P7 protein: Cleaved by ER signal peptidase and forms an ion channel. This viroporin protein is essential for efficient assembly and release of infectious virions but not for cell entry. 5/19/2022 15

16. Virology… Viral Protein Function NS2 Complexes with NS3 to form a cysteine protease NS3 Functions as serine protease portion of the NS3 protein functions as a helicase NS4A complexes with NS3 and functions to stabilize the protease and helicase NS4B Membranous Web formation NS5A Essential for viral replication and is believed to provide an RNA-binding site within the replication complex NS5B RNA dependent RNA Polymerase 5/19/2022 16

17. Virology… Genotypes and Quasispecies: HCV has an inherently high mutational rate that results in considerable heterogeneity throughout the genome. This high mutational rate is in part a consequence of the RdRp of HCV, which lacks 3′- to 5′-exonuclease proofreading ability An average of one error occurs for every 10 4 to 10 5 nucleotides copied. This phenomenon is favored by a high viral turnover rate; 10 10 to 10 12 virions are produced per day. 5/19/2022 17

18. Virology… Genotypes and Quasispecies: Nucleotide sequencing has shown variation of up to 34% between genotypes The most conserved region (5′ UTR) has a maximum nucleotide sequence divergence of 9% The sequences cluster into 7 major genotypes 60% to 70% and More than 67 subtypes within these major genotypes, with sequence similarities of 77% to 80%. 5/19/2022 18

19. Virology… Genotype Geographic Distribution 1a USA,Europe 1b USA,Europe 1c USA,Europe 2 USA 3 Europe,USA 4 Middle East,Egypt,Central Africa 5 South Africa, Europe(France and Belgium),Middle East(Lebanon and Syria) 6 Predominantly in Asia 5/19/2022 19

20. 5/19/2022 20 Source: The Polaris Observatory HCV Collaborators

21. Virology… 5/19/2022 21

22. Virology… Genotypes and Quasispecies: Quasispecies are closely related, yet heterogeneous, sequences of HCV RNA within a single infected person that result from mutations that occur during viral replication The rate of nucleotide changes varies significantly among the different regions of the viral genome The highest proportion of mutations are found in the E1 and E2 regions, particularly in HVR1 The development of quasispecies may be one mechanism by which the virus escapes the host’s immune response and establishes persistent infection . 5/19/2022 22

23. 5/19/2022 23

24. Virology… Genotypes and Quasispecies: In acute disease, patients in whom genetic variation in the HVR1 region develops after antibody seroconversion progress to chronic disease Quasispecies formation results from antibody-mediated immune pressure An increased number of quasispecies has also been associated with more rapid progression to cirrhosis and the development of HCC 5/19/2022 24

25. Epidemiology Incidence and Prevalence: The worldwide prevalence of HCV infection, based on detection of HCV RNA in serum, is estimated to be 1%, with more than 71 million people infected chronically. The highest seroprevalence in different age groups shifted from 35 to 44 years (2.5%) to 55 to 64 years in 2005 (2.7%) The prevalence is higher in males (2.1%) than in females (1.1%), and in African Americans (3%) than in whites (1.5%) . 5/19/2022 25

26. 5/19/2022 26

27. 5/19/2022 27

28. 5/19/2022 28

29. Epi… Worldwide, 3 different epidemiologic patterns of HCV infection have emerged: Previous exposure through health care with a peak prevalence in older persons Exposure through injection drug use, the major risk factor since data first became available in about 1960, with a peak prevalence among middle-aged persons; and Ongoing high levels of infection in areas where high rates of infection occur in all age groups. 5/19/2022 29

30. Epi… Transmission: Percutaneous transmission Blood transfusion Needlestick inocculation Non Percutaneous transmission Sexual contact Perinatal exposure Sporadic HCV infection 5/19/2022 30

31. Pathogenesis Determinants of persistence of HCV include: Inadequate induction of the innate immune response Insufficient induction or maintenance of an adaptive immune response The production of viral quasispecies and The induction of immunologic tolerance or exhaustion . 5/19/2022 31

32. Patho… Chronic hepatitis develops in 50% to 90% of persons with acute HCV infection In the minority of patients in whom acute HCV resolves spontaneously This response can be detected up to 20 years after resolution of infection Immune response is essential in preventing viral persistence, in those without viral clearance the immune response mediates hepatic cell destruction and fibrosis. 5/19/2022 32

33. Patho… Viral Mechanisms: In chronically infected patients, the pathogenesis of liver damage is largely immune mediated. In a small subset of immunocompromised HCV-infected patients a syndrome termed fibrosing cholestatic hepatitis develops The majority of patients with HCV infection have a variable immune response 5/19/2022 33

34. Patho… Immune-Mediated Mechanisms: HCV infection elicits an immune response involves both innate and adaptive immunity The innate response includes natural killer (NK) cell activation and cellular antiviral mechanisms triggered by PAMPs recognized by the cell These processes can lead to apoptosis of infected cells within the first few hours of infection NK cells, as the effector cells of the innate immune system, also produce TNF-β and IFN-α 5/19/2022 34

35. Patho… Immune-Mediated Mechanisms: NK cell function is slowed because of production of cytokines are interrupted when the HCV E2 protein binds its cellular receptor CD81 PAMPs activate several cellular processes, including the JAK-STAT (Janus kinase‒signal transducer and activator of transcription) proteins pathway and Toll-like receptor-3 NS3/4 protease Degrades TRIF, an essential intermediate in this pathway, and Cleaves IFN promoter stimulator-1, an intermediate in the signaling cascade, to block activation of IFN when retinoic inducible gene-1 binds viral intermediates. 5/19/2022 35

36. Patho… Immune-Mediated Mechanisms: NS5A and E2 both can disrupt protein kinase R function to suppress translation, thereby allowing viral replication to continue. NS5A inhibits 2′-5′-oligoadenylate synthetase, which is expressed in response to HCV infection and leads to HCV RNA degradation. Taken together, HCV is able to disrupt the innate immune response at several levels, thereby establishing chronicity of infection. 5/19/2022 36

37. Patho… Immune-Mediated Mechanisms: Cellular immune response plays a pivotal role in the pathogenesis of HCV infection, the importance of the humoral immune response is less clear Antibodies to viral proteins are produced and do not appear to correlate with the stage of infection or immune reactivity Administration of high-titer HCV-enriched or HCV-specific Ig has little effect on viral levels or persistence in humans. Both the virus and the immune response probably play a role in the development of hepatocellular injury. 5/19/2022 37

38. Clinical Features Acute Hepatitis C : HCV accounts for an estimated 20% of cases of acute hepatitis Within 7 to 21 days after viral transmission, HCV RNA becomes detectable in serum HCV RNA levels rise rapidly in serum, followed by a delayed increase in serum ALT levels 4 to 12 weeks, indicative of hepatic injury Serum ALT levels frequently reach values more than 10x, with concomitant rises in the serum bilirubin level in some inidividuals 5/19/2022 38

39. Clinical… 5/19/2022 39 www.cdc.gov/hepatitis/Resources/Professionals/Traini ng /Serology/training.htm

40. Clinical… Acute Hepatitis C : Commonly reported symptoms include fatigue, nausea, abdominal pain, loss of appetite, mild fever, itching, and myalgia Jaundice, which is the most specific liver-related symptom, develops in 50% to 84% of patients with clinically overt acute HCV infection Clinical course apparent and the more severe when acute HCV infection occurs in patients who drink large amounts of alcohol or have coinfection with HBV or HIV Age and gender clearly influence the risk of chronicity, with younger and female patients having the lowest rates of chronicity. 5/19/2022 40

41. Clinical… Acute Hepatitis C : Other factors that may play a role include the Source of infection and size of inoculum Immune status of the host The patient’s race The rate of spontaneous clearance is higher in symptomatic patients Single nucleotide polymorphisms (SNPs) close to the IFN lambda-3, or interleukin 28B, gene (IFN-λ3, IL28B) have been found to be associated with the outcome of acute hepatitis C. 5/19/2022 41

42. Clinical… Chronic Hepatitis C: Serum ALT levels are usually elevated in patients with chronic HCV infection The ALT level may remain normal for prolonged periods of time in about 20% of cases, although transient elevations occur even in these cases Persistently normal ALT levels are more common in women, and such cases typically are associated with lower serum HCV RNA levels Most patients with chronic hepatitis C are asymptomatic before the onset of advanced hepatic fibrosis Patients often complain of nonspecific symptoms such as fatigue, vague abdominal pain, or depression, and they consistently score lower than HCV negative in HRQOL 5/19/2022 42

43. Clinical… Extrahepatic Manifestations: Types 2 and 3 cryoglobulinemia , Characterized by polyclonal IgG plus monoclonal IgM and polyclonal IgG plus polyclonal IgM, respectively Among HCV-infected patients, 19% to 50% have cryoglobulins in serum Clinical manifestations of cryoglobulinemia are reported in only 5% to 10% of these patients Symptoms and signs include fatigue, arthralgias, arthritis, purpura, Raynaud phenomenon, vasculitis, peripheral neuropathy, and nephropathy The diagnosis is clear when a rheumatoid factor is detected, cryoglobulins are present, and complement levels are low in serum 5/19/2022 43

44. Clinical… Extrahepatic Manifestations: Treatment of the underlying HCV infection should be considered in patients with symptomatic cryoglobulinemia. Consensus guidelines recommend treatment of extrahepatic manifestations with IFN-free DAA regimens In addition,monoclonal antibody therapy targeting B cells (anti-CD20 therapy with rituximab) has been shown to be useful for HCV-related cryoglobulinemia , 5/19/2022 44

45. Clinical… Extrahepatic Manifestations: Patients with vasculitis due to HCV infection may benefit from low-dose interleukin-2 therapy Type 2 cryoglobulinemia evolves into lymphoma over time in 8% to 10% of patients HCV shows lymphotropism and may facilitate the development and selection of abnormal B-cell clones by chronic stimulation of the immune system. 5/19/2022 45

46. Clinical… Extrahepatic Manifestations: Seropositivity for autoantibodies ANA with a titer greater than 1:40 in 9%, ASMA with a titer greater than 1:40 in 20%, LKM abs in 6% The diagnosis of an autoimmune condition in a patient with HCV infection can never be based on serology alone. 5/19/2022 46

47. 5/19/2022 47 N Engl J Med 2021;384:1038-52. D

48. 5/19/2022 48

49. Clinical… 5/19/2022 49

50. Diagnosis Indirect Assays Direct Assays Genotype Testing 5/19/2022 50

51. Dx… Indirect Assays: EIAs detect antibodies against different HCV antigens The third-generation EIAs detect antibodies against HCV core, NS3, NS4, and NS5 antigens as early as 7 to 8 weeks after infection Despite ongoing viral replication, serologic test results can be negative in patients who are on hemodialysis or are immunocompromised Instead, patients who are anti-HCV positive should undergo HCV RNA testing to determine if they have active viremia or have cleared the infection.  5/19/2022 51

52. Dx… Direct Assay: Quantitative, highly sensitive, “real-time” HCV RNA tests represent the state of the art for determining HCV viremia in antiHCV–positive persons The lower limit of detection of most assays varies from 10 to 15 international units (IU)/ mL Transcription-mediated amplification is also extremely sensitive, but available assays are not quantitative in the lower dynamic range of the test: Positivity within 1 to 3 weeks after acute infection and Detection of low-level residual infection during antiviral therapy. 5/19/2022 52

53. Dx… Direct Assay… Although conversion to a standard IU/ mL concentration attempted to resolve such discrepancies, results are still variable Reported conversion factors vary from 0.9 copies/ mL to 5.2 copies/ mL per IU/ mL For this reason, the same laboratory and assay are recommended during antiviral treatment monitoring 5/19/2022 53

54. Dx… Direct Assay: A cheaper and faster alternative to nucleic acid testing for HCV RNA to confirm HCV viremia is the HCV core antigen assay . The assay cannot be used to monitor response to antiviral therapy and make decisions regarding therapy If viremia needs just to be confirmed, however, HCV core antigen testing is a reasonable alternative to HCV RNA testing 5/19/2022 54

55. Dx… HCV genotype: Some DAA regimens are only recommended for certain HCV genotypes and subtypes. HCV genotyping can be accomplished by several methods. The most accurate approach uses PCR methodology and direct sequencing of the NS5B or E1 region HCV genotyping can be performed by evaluating type-specific antibodies (90% concordance in immunocompetent patients). 5/19/2022 55

56. Dx… HCV genotype: Testing can also be accomplished with reverse hybridization to genotype-specific probes, restriction fragment length polymorphism analysis, or PCR amplification of the 5′ noncoding region of the HCV genome. These tests have 92% to 96% concordance with the correct genotype; genotype 1 is identified with the highest accuracy. A line-probe assay (INNO- LiPA ) using genotype-specific probes for reverse transcription of the 5′ portion of the HCV genome is the most popular commercial assay for HCV genotyping.  5/19/2022 56

57. Dx… 5/19/2022 57 AASLD/IDSA and CDC

58. Dx… 5/19/2022 58 AASLD/IDSA and CDC

59. Dx… 5/19/2022 59 https://www.hcvguidelines.org/references/cdc-2013

60. Non Invasive Assesment of Fibrosis Assessment of the degree of liver injury is recommended in all patients with HCV infection. For many years, this assessment was performed by percutaneous liver biopsy but noninvasive methods are now used for initial assessment of liver fibrosis stage Several histologic scoring systems have been used to quantify hepatic injury into discrete grades of inflammation and stages of fibrosis. 5/19/2022 60

61. Non Invasive… The first system used was the Histology Activity Index described by Knodell and colleagues. periportal inflammation and necrosis (graded as 0 to 10), lobular inflammation and necrosis (0 to 4), portal inflammation (0 to 4), fibrosis (0 to 4). This scoring system combines inflammation and fibrosis into one score. 5/19/2022 61

62. Non Invasive… Scheuer created a simplified scoring system that separates grade of inflammation from stage of fibrosis: portal inflammation and interface hepatitis (0 to 4), lobular activity (0 to 4), and fibrosis stage (0 to 4). 5/19/2022 62

63. Non Invasive… The Ishak system is a modification of Knodell’s system Ishak’s fibrosis scores range from 0 to 6 1 or 2( portal fibrotic expansion) 3 or 4( bridging fibrosis) 5 or 6 (cirrhosis) The higher number of stages of fibrosis has made the Ishak system popular for scoring progression of fibrosis in clinical trials. 5/19/2022 63

64. Non Invasive… The METAVIR scoring system is the most popular in practice. Inflammation is graded from 0 to 4(none, mild, moderate, and severe), and Fibrosis is staged from 0 to 4 Portal fibrotic expansion(1); Portal fibrosis with septa formation(2) Bridging fibrosis(3) Cirrhosis(4) 5/19/2022 64

65. Non Invasive… 5/19/2022 65

66. Non Invasive… Examination of liver biopsy specimens is still considered the gold standard for establishing the grade of inflammation and stage of fibrosis, limitations of liver biopsy include: Associated morbidity Cost; Poor patient acceptance; Intraobserver and interobserver variability Inaccuracy in the interpretation of findings, Sampling error 5/19/2022 66

67. Non Invasive… 5/19/2022 67

68. Non Invasive… 5/19/2022 68

69. Non Invasive… The AST-to-platelet ratio index (APRI) is used primarily to diagnose or exclude cirrhosis. In an initial evaluation, 81% of cirrhotic patients were accurately excluded with an APRI score of 0.5 or less Transient elastography (FibroScan) to assess liver stiffness, which correlates with the amount of hepatic fibrosis. Combining transient elastography with serum markers increases the accuracy of predicting fibrosis and cirrhosis 5/19/2022 69

70. Non Invasive… 5/19/2022 70

71. Non Invasive… 5/19/2022 71

72. Non Invasive… In patients undergoing initial assessment of chronic hepatitis C. determination of the stage of liver fibrosis, either by liver biopsy or noninvasive methods, is recommended Liver biopsy is not required when cirrhosis is already suggested by clinical findings It is also not indicated following successful antiviral therapy, although histology generally improves significantly over time following eradication of HCV 5/19/2022 72

73. Non Invasive… 5/19/2022 73 Diagnostic algorithm for investigating the presence of cirrhosis in patients with chronic liver disease.

74. Natural History Chronic hepatitis C can cause continuous liver damage, resulting in liver cirrhosis and subsequently HCC Most liver-related symptoms are restricted to patients with advanced cirrhosis The most feared complication of chronic HCV infection is liver-related mortality due to decompensated liver cirrhosis or development of HCC In a meta-analysis, cirrhosis developed on average in 16% of patients within 20 years after the onset of HCV infection Cirrhosis was attributable to HCV infection in 27% of cases 5/19/2022 74

75. Natural hx… Age is one of the most important risk factors for fibrosis progression in chronic HCV infection A longer duration of infection has also been associated with a higher stage of liver fibrosis Overall, the development of HCV related cirrhosis seems to be a dynamic process that accelerates exponentially with increasing age The mechanisms by which progression of fibrosis accelerates with aging are not well defined. Changes in the regenerative capacity of the liver, Alterations in the immune system, and Telomere shortening may play roles. 5/19/2022 75

76. Natural hx… Female gender seems to be protective, and fibrosis progression is much faster in HCV-infected men Genetic factors also play a role in the development of cirrhosis Histologic activity and the frequency of cirrhosis are lower in African Americans than in Caucasians. 5/19/2022 76

77. Natural hx… Elevated serum ALT levels during chronic hepatitis C are associated with an increased risk of liver fibrosis progression. Lower progression rates of fibrosis are reported in patients with normal serum ALT levels Accelerated disease progression in patients infected with HCV genotype 3 5/19/2022 77

78. Natural hx… Flares of hepatitis seem to occur more frequently in HCV genotype 2 infection and may result in a more severe course of liver disease. Viral load is not related to the degree of liver damage or fibrosis . Hepatic steatosis is a histologic hallmark of chronic hepatitis C. Several studies have shown that steatosis is linked to the stage of liver fibrosis in patients with chronic HCV infection The strongest association exists between HCV genotype 3 infection and steatosis 5/19/2022 78

79. Natural hx… Mild to moderately increased hepatic iron stores are associated with more advanced liver fibrosis. Excessive alcohol consumption is clearly an independent major cause of cirrhosis Coffee consumption has been reported to have a beneficial effect on overall mortality from HCV infection in population-based studies, Freedman and colleagues have also shown that Greater coffee consumption correlates with a lower stage of liver fibrosis, reduced fibrosis progression, Less steatosis and insulin resistance, Lower serum ALT levels; Best outcomes occur in persons who drink 3 or more cups per day 5/19/2022 79

80. Natural hx… HCC: chronic hepatitis C is responsible for approximately 25% of cases of HCC worldwide, with particularly high prevalence rates in East Asia In contrast to chronic hepatitis B, HCC due to HCV usually does not develop in noncirrhotic livers The risk is much higher in patients with cirrhosis, with a rate of 1.4% to 4.9% per year. The overall 5-year risk of HCC has been reported to be as high as 7% to 30% in patients with HCV-related cirrhosis. 5/19/2022 80

81. Natural hx… HCC is frequently the first clinical complication of HCV related cirrhosis and often occurs before hepatic decompensation becomes evident. Risk factors for the development of HCC in patients with chronic HCV infection are similar to those associated with the development of cirrhosis. older age and male gender and substantial alcohol consumption are well-established risk factors. Type 2 diabetes mellitus has been identified as an important independent risk factor. Coinfection with HBV Genetic factors also contribute to the development of HCC. 5/19/2022 81

82. Natural hx… 5/19/2022 82

83. Natural hx… 5/19/2022 83

84. Treatment 5/19/2022 84

85. Treatment 5/19/2022 85

86. Tx… 5/19/2022 86

87. Tx… 5/19/2022 87

88. 5/19/2022 88 What made DAAs Revolutionary?

89. Tx… All oral IFN-free Highly efficacious (>95% SVR) Well tolerated High barriers to resistance, Simple dosing, Low pill burdens, Treatment durations as brief as 8–12 weeks, Pangenotypic efficacy 5/19/2022 89 What made DAAS Revolutionary?

90. Treatment 5/19/2022 90

91. 5/19/2022 91

92. Tx… 5/19/2022 92

93. Tx… 5/19/2022 93

94. Tx… Factors affecting drug selection: HCV genotype Prior treatment experience Presence of cirrhosis and severity of liver disease Potential for drug–drug interactions Renal function Presence of baseline resistance-associated variants (RAVs) 5/19/2022 94

95. Simplified Treatment for Tx naïve Adults without Cirrhosis 5/19/2022 95

96. Tx… 5/19/2022 96

97. Tx… Pretreatment Assessment Cirrhosis assessment Medication reconciliation Potential drug-drug interaction assessment Education 5/19/2022 97

98. Tx… Pretreatment laboratory testing: Within 6 months of initiating treatment: Complete blood count (CBC) Hepatic function panel ( ie , albumin, total and direct bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST]) Calculated glomerular filtration rate (eGFR) Any time prior to starting antiviral therapy: Quantitative HCV RNA (HCV viral load) HIV antigen/antibody test Hepatitis B surface antigen Before initiating antiviral therapy : Serum pregnancy testing and counseling about pregnancy risks of HCV medication should be offered to women of childbearing age. 5/19/2022 98

99. Tx… Recommended Regimens Glecaprevir (300 mg) / pibrentasvir (120 mg) to be taken with food for a duration of 8 weeks Sofosbuvir (400 mg) / velpatasvir (100 mg) for a duration of 12 weeks 5/19/2022 99

100. Simplified Treatment for Tx naïve Adults with Compensated Cirrhosis 5/19/2022 100

101. Tx… 5/19/2022 101

102. Tx… Recommended Regimens Genotype 1-6 : Glecaprevir (300 mg) / pibrentasvir (120 mg) to be taken with food for a duration of 8 weeks   Genotype 1, 2, 4, 5, or 6 Sofosbuvir (400 mg) / velpatasvir (100 mg) for a duration of 12 weeks Patients with genotype 3 require baseline NS5A resistance-associated substitution (RAS) testing. Those  without  Y93H can be treated with 12 weeks of sofosbuvir/velpatasvir. 5/19/2022 102

103. Tx… 5/19/2022 103

104. Tx… 5/19/2022 104

105. 5/19/2022 105

106. How efficacious are HCV Treatments? 5/19/2022 106

107. Tx… 5/19/2022 107

108. 5/19/2022 108

109. 5/19/2022 109

110. Tx… 5/19/2022 110

111. Tx… 5/19/2022 111 AASLD/IDSA

112. Tx… 5/19/2022 112

113. Tx… Drug-Drug Interactions: Amiodarone , which can cause severe bradycardia with sofosbuvir containing regimens Strong cytochrome P450 inducers Statins , which can increase to toxic levels with protease inhibitor regimens Ethinyl estradiol–containing OCPs and certain chemotherapy medications that may also be increased by protease inhibitors Proton-pump inhibitors that may reduce the absorption of certain NS5A inhibitors 5/19/2022 113

114. Tx… 5/19/2022 114

115. Tx… 5/19/2022 115

116. Tx… 5/19/2022 116

117. Tx… 5/19/2022 117

118. Unique and Key Sub-Populations 5/19/2022 118

119. Tx… HIV/HCV co-infection The success rate and tolerance of DAA therapy for persons co infected infected with HIV and HCV are identical to those of HCV mono infected persons The only special considerations required in HIV/HCV co-infected persons are drug–drug interactions of HCV DAA and antiretroviral therapy regimens 5/19/2022 119

120. Tx… 5/19/2022 120

121. Tx… HBV/HCV Co-infection Hepatitis C typically suppresses hepatitis B replication in patients who are co-infected. Patients who are HBsAg-positive should be treated with an HBV-directed DAA (entecavir or tenofovir) during and after HCV treatment. Patients who are HBsAg negative but HBc Ab -positive have less than 1% risk for HBVr, which can occur years after HCV treatment These patients should be routinely monitored for HBVr for at least 24 weeks after completion of HCV treatment and if liver test results become abnormal thereafter. 5/19/2022 121

122. Tx… Decompensated cirrhosis Interferon-based treatments and protease inhibitors are contraindicated Candidacy for liver transplant must be assessed Drug options for patients with decompensated cirrhosis are sofosbuvir– velpatasvir or sofosbuvir– ledipasvir 5/19/2022 122

123. Tx… Decompensated cirrhosis For treatment-naive patients with decompensated cirrhosis a 12-week course of sofosbuvir– ledipasvir or sofosbuvir–velpatasvir plus weight-based ribavirin results in cure in more than 85% of cases For noncandidates for ribavirin, sofosbuvir–velpatasvir or sofosbuvir– ledipasvir can be used for 24 weeks without ribavirin. For patients with decompensated cirrhosis who are experienced with either sofosbuvir or an NS5A inhibitor, sofosbuvir–velpatasvir or sofosbuvir– ledipasvir plus ribavirin for 24 weeks. 5/19/2022 123

124. Tx… HCV and Renal Impairment No dose adjustment for GFR ≥ 30 The fixed-dose combination of Glecaprevir and pibrentasvir and Grazoprevir and elbasvir (for 1b)are the preferred choices in patients with eGFR <30 ml/min/1.73 m2 The risks and benefits of treatment before transplant must be individualized 5/19/2022 124

125. 5/19/2022 125

126. Tx… Pregnancy: 5/19/2022 126

127. Tx… 5/19/2022 127

128. Tx… 5/19/2022 128

129. References Sleisenger and Fordtrans’ Gastrointestinal and Liver Disease(11 th edition) AASLD/IDSA,2021 Harrison’s Principles of Internal Medicine(20 th edition) Practical Gastroenterology and Hepatology(2 nd edition) Uptodate,2018 Lancet 2019; 394: 1451–66 WHO Guidelines For The Care and Treatment Of Persons Diagnosed With Chronic Hepatitis C Virus(2018) 5/19/2022 129

130. Thank You!!! 5/19/2022 130