Hepatitis c

epidemiology, clinical features and treatment

1. Hepatitis C Dr Avatar Verma MD Resident CMSTH

2. Global Burden of Hepatitis C Hepatitis C is major public health problem worldwide About 180 million people are infected with hepatitis C virus It account for 3 percent of global population 3-4 million people become infected with HCV annually About 25 million people are infected in Europe HCV prevalence 5 times exceeds HIV prevalence

3. Global Burden of Hepatitis C More then 350 000-500 000 people die every year from Hepatitis C related end-stage liver disease (cirrhoses, HCC, liver failure) Hepatitis C infection is top priority problem in many A frican countries (as high as 14.5% in Egypt ) and Asian countries ie . India (1.5%), Japan (1.2%), Malaysia (2.3%), and Philipines (2.3%)

4. Hepatitis C virus before its identification was labeled “non-A, non-B hepatitis,” Linear, single-strand, positive-sense, 9600-nucleotide RNA virus Only member of the genus Hepacivirus in the family Flaviviridae Genome contains a single, large open reading frame (gene) that codes for virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield 10 viral proteins

5. At least six distinct major genotypes (and a minor genotype 7), as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing Genotypes differ from one another in sequence homology by ≥30%, and subtypes differ by approximately 20% Because divergence of HCV isolates within a genotype or subtype and within the same host may vary insufficiently to define a distinct genotype, these intragenotypic differences are referred to as quasispecies The genotypic and quasispecies diversity of HCV, resulting from its high mutation rate, interferes with effective humoral immunity Neutralizing antibodies to HCV have been demonstrated, but they tend to be short lived, and HCV infection does not induce lasting immunity against reinfection with different virus isolates or even the same virus isolate

6. Thus, neither heterologous nor homologous immunity appears to develop commonly after acute HCV infection Some HCV genotypes are distributed worldwide, whereas others are more geographically confined In addition, differences exist among genotypes in responsiveness to antiviral therapy but not in pathogenicity or clinical progression (except for genotype 3, in which hepatic steatosis and clinical progression are more likely)

7. HCV genotype distribution

8. Pathogenesis The virus replicates mainly in the hepatocytes of the liver, where it is estimated that daily each infected cell produces approximately fifty virions (virus particles) The virus may also replicate in peripheral blood mononuclear cells, potentially accounting for the high levels of immunological disorders found in chronically infected HCV patients

9. To enter the host cell, HCV E2 and E1 proteins recognize and bond with the CD81 receptors present on the surface of hepatocytes and lymphocytes HCV enters cell through endocytosis In the cytoplasm, the messenger RNA then undergoes translation, and polyproteins are processed; HCV RNA then replicates, after which the new viral 'RNA's are packaged and transported to the surface of the host cell so that they can disseminate and complete a new cycle

10. Transmission routes of HCV Transfussion of infected blood or its products, using nonsterile syringes, needles and medical instruments, transplantation of infected donor organs or tissues, occupational exposure with infected blood Parenteral Risk of sexual transmission of HCV is very low. In monogamous partners about 2%. The risk is higher among persons having multiple sexual partners about 4-6% (commercial sex workers, men who have sex with men etc.) Sexual Mother to child Chance of Vertical transmission of HCV is about 5-7 %. The risk is increased if HCV viral load in mother’s blood is high HCV is not transmitted by air, droplets , vectors or from animals.

11. Acute HCV Asymptomatic 75% Without Jaundice Jaundice recovery 10% ? ? ? Chronic Infection 70- 85 % Recovery 50%-52% Symptomatic 25% recovery 15- 30% Natural History

12. Natural history of Hepatitis C Acute HCV Infection 60-85 % Persistent infection 15-40 % Recovery 20-40% cirrhoses 4-5% HCC

13. Why HCV infection is predominantly chronic? HCV has ability to “escape” immune response of the host HCV is characterized by rapid and permanent changes in its antigenic structure; antigenic structure changes occur multiple times per minute variability of this virus makes T and B lymphocytes unable to identify and respond to these permanently changed antigens Antigenic variations of HCV in the same host is called ( quasispecies ), number of such quasispecies reaches about 10 10 – 10 11 per day Due to variability of HCV “Time competition” between new antigenic strains and the speed of neutralizing antibodies develops

14. Clinical Manifestations Incubation period: 15–160 days (mean, 7 weeks) Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias , myalgias , headache, photophobia, pharyngitis , cough, and coryza may precede the onset of jaundice by 1–2 weeks Dark urine and clay-colored stools may be noticed by the patient from 1–5 days before the onset of clinical jaundice

15. With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish, but in some patients, mild weight loss (2.5–5 kg) is common and may continue during the entire icteric phase The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction Splenomegaly and cervical adenopathy are present in 10–20% of patients with acute hepatitis Rarely, a few spider angiomas appear during the icteric phase and disappear during convalescence During the recovery phase, constitutional symptoms disappear, but usually some liver enlargement and abnormalities in liver biochemical tests are still evident

16. The duration of the posticteric phase is variable, ranging from 2–12 weeks, and is usually more prolonged Complete clinical and biochemical recovery is to be expected 3–4 months after the onset of jaundice in three-quarters of uncomplicated cases Hepatitis C is self limited in only ~15% Chronic hepatitis is generally present as fatigue otherwwise are assymptomatic and slowly progressive well compensated untill signs of decompensation occurs

17. Laboratory Features Complete Blood count Transient neutropenia and lymphopenia followed by lymphocytosis Deranged liver function test Increased transaminase mostly ALT Increase in both conjugated and uncojugated bilirubin fractions Mild increase in ALP and γ globulin Raised PT

18. During acute phase, antibodies to smooth muscle and other cell constituents may be present, and low titers of RF, nuclear antibody, and heterophile antibody can also be found Antibodies to LKM may occur; however, the species of LKM is different from LKM characteristic of autoimmune hepatitis type 2 The presence of anti-HCV supports a diagnosis of acute hepatitis C Occasionally, testing for HCV RNA or repeat anti-HCV testing later during the illness is necessary to establish the diagnosis Anti-HCV supports and HCV RNA testing establishes the diagnosis of hepatitis C

19. Interpretation of HCV Assays Anti HCV HCV RNA Interpretation Positive Positive Acute or chronic HCV depending on the clinical context Positive Negative Resolution of HCV; Acute HCV during period of low-level viremia . Negative Positive Early acute HCV infection; chronic HCV in setting of immunosuppressed state; false positive HCV RNA test Negative Negative Absence of HCV infection 25

20. Complications Hepatitis C is less severe during the acute phase than hepatitis B and is more likely to be anicteric Chronic hepatitis is more likely in older age, longer duration of infection, advanced histologic stage and grade, more complex quasispecies diversity, increased hepatic iron, concomitant other liver disorders (alcoholic liver disease, chronic hepatitis B, hemochromatosis , α1 antitrypsin deficiency, and steatohepatitis ), HIV infection, and obesity Cirrhosis (20% within 10–20 years of acute illness) accelerated by concomitant HIV infection, other causes of liver disease, excessive alcohol use, and hepatic steatosis

21. Hepatocellular carcinoma in cirrhotic patients with hepatitis C is 1−4%, in patients who have had HCV infection for 30 years or more EMC (Essential mixed cryoglobulinemia ) is an immune-complex disease that can complicate chronic hepatitis C and is part of a spectrum of B cell lymphoproliferative disorders Cutaneous vasculitis and membranoproliferative glomerulonephritis as well as lymphoproliferative disorders such as B-cell lymphoma and unexplained monoclonal gammopathy

22. Sjogren’s syndrome, lichen planus , porphyria cutanea tarda , type 2 diabetes mellitus, and the metabolic syndrome (including insulin resistance and steatohepatitis )

23. Definition of responses Rapid virological response (RVR) HCV RNA negative at treatment week 4 by a sensitive PCR based quantitative assay Early virological response (EVR) ≥2 log reduction in HCV RNA level compared to baseline HCV RNA level (partial EVR) or HCV RNA negative at treatment week 12 (complete EVR) End-of-treatment response (ETR) HCV RNA negative by a sensitive test at the end of treatment 31

24. Sustained virological response (SVR) HCV RNA is undetectable at the end of treatment and remains undetectable 24 weeks after completion of treatment Breakthrough On-treatment presence of detectable HCV RNA on 2 consecutive serum tests conducted after a previous on-treatment serum test showed an undetectable level of HCV RNA Relapsers Virological response occurred; the patient became HCV RNA undetectable, and remained negative through the end of treatment, but relapse occurred after discontinuation of treatment. 32

25. Nonresponder Patient who never achieved an undetectable of HCV RNA during or at the end of treatment . Null responder Failure to decrease HCV RNA by 2 logs after 12 week of therapy Partial responder Two log decrease in HCV RNA but still HCV RNA positive at week 24 Slow responder During treatment, the HCV RNA shows a decline, but does not become negative until after 12 weeks of treatment 33

26. Virologic responses during a 48-week course of antiviral therapy in patients with hepatitis C, genotype 1 or 4 (for genotypes 2 or 3, the course would be 24 weeks). 34

27. Treatment SVR= Cure Till 2001 to 2011 standard of care dual therapy with PEG-Interferon + Ribavirin In 2011 DAA (direct acting antiviral) were introduced Telaprevir and Boceprevir Direct-acting antivirals (DAAs), are medications targeted at specific steps within the HCV life cycle DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection

28. HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. 2007 Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly NS3/4A protease inhibitors NS5B polymerase inhibitors NS5A inhibitors “Previr’s” Boceprevir, Telaprevir, Simeprevir, Faldaprevir “Buvir’s” Sofosbuvir, Deleobuvir “Asvir’s” Daclatasvir, Ledipasvir DAA Uncoating Receptor binding

29. Recommended Assessments Prior to Starting Antiviral Therapy Staging of hepatic fibrosis is essential prior to HCV treatment Following laboratory tests are recommended within 12 weeks prior to starting antiviral therapy: Complete blood count (CBC) INR Hepatic function panel (albumin, total and direct bilirubin , alanine aminotransferase , aspartate aminotransferase , and alkaline phosphatase levels) Calculated glomerular filtration rate (GFR) Thyroid-stimulating hormone (TSH) if IFN is used  

30. The following laboratory testing is recommended at any time prior to starting antiviral therapy: HCV genotype and subtype Quantitative HCV RNA (HCV viral load) Patients scheduled to receive an HCV NS3 protease inhibitor ( previr ) assessed for history of decompensated liver disease and for severity of liver disease using CTP score. Patients with current or prior history of decompensated liver disease or with a current CTP score of 7 or greater should NOT receive treatment with regimens that contain NS3 protease inhibitors due to lack of safety data Similarly, CTP score of 5 or 6, who cannot be closely monitored for during treatment, should not receive paritaprevir / ritonavir

31. All patients initiating HCV DAA therapy should be assessed for HBV coinfection with HBsAg , anti-HBs, anti- HBc and for resistance-associated variants (RAV)

32. Treatment regimens EASL 2016

33. PATIENTS WITH DECOMPENSATED CIRRHOSIS Patients with HCV genotype 1 or 4 infection who have decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) who may or may not be candidates for liver transplantation, including those with hepatocellular carcinoma Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks Daily fixed-dose combination of sofosbuvir (400 mg)/ velpatasvir (100 mg) with weight-based ribavirin | for 12 weeks Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks

34. Genotype 1 or 4 patients with decompensated cirrhosis who are ribavirin Ineligible or prior sofosbuvir -based treatment has failed Daily fixed-dose combination of sofosbuvir (400 mg)/ velpatasvir (100 mg) for 24 weeks   Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) for 24 weeks

35. HCV genotype 1 or 4 infection who have decompensated cirrhosis or prior sofosbuvir -based treatment has failed Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 24 weeks Daily fixed-dose combination of sofosbuvir (400 mg)/ velpatasvir (100 mg) with weight-based ribavirin ||   for 24 weeks  

36. HCV genotype 2 or 3 infection who have decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) and who may or may not be candidates for liver transplantation, including those with hepatocellular carcinoma Daily fixed-dose combination sofosbuvir (400 mg)/ velpatasvir (100 mg) with weight-based ribavirin for 12 weeks Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks

37. In patients with renal impairment For patients with mild to moderate renal impairment ( CrCl 30 mL /min-80 mL /min), No dosage adjustment is required when using Daclatasvir (60mg*), Fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg), Sofosbuvir (400mg)/ velpatasvir (100mg), or paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) with twice-daily dosed dasabuvir (250 mg), simeprevir (150 mg), or sofosbuvir (400 mg) to treat or retreat HCV infection in patients with appropriate genotypes

38. Creatinine clearance [ crcl ] <30 ml/min) or end-stage renal disease (ESRD) for whom treatment has been elected before kidney transplantation: Genotype 1a, or 1b, or 4 Daily fixed-dose combination of elbasvir (50 mg)/ grazoprevir (100mg) for 12 weeks Genotype 1b Daily fixed-dose combination of paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks Genotype 2, 3, 5, or 6 PEG-IFN and dose-adjusted ribavirin (200 mg daily)

39. HIV coinfection Daclatasvir requires dose adjustment with ritonavir -boosted atazanavir (a decrease to 30 mg daily) and efavirenz or etravirine (an increase to 90 mg daily) Elbasvir / grazoprevir and Simeprevir should be used with antiretroviral drugs with which it does not have clinically significant interactions: abacavir , emtricitabine , enfuvirtide , lamivudine , maraviroc , raltegravir , dolutegravir , rilpivirine , and tenofovir Daily fixed-dose combination of Sofosbuvir / Velpatasvir (100 mg) or Ledipasvir (90 mg)/ Sofosbuvir (400 mg) can be used with most antiretrovirals , but not efavirenz or etravirine Tenofovir alafenamide (TAF) may be an alternative to TDF treatment for patients who take cobicistat or ritonavir as part of their antiretroviral therapy

40. Recommended Follow-up for Patients Who Achieve a Sustained Virologic Response (SVR) For patients who do not have advanced fibrosis ( ie , those with Metavir stage F0-F2), recommended follow-up is the same as if they were never infected with HCV In such cases, a quantitative HCV RNA assay rather than an anti-HCV serology test is recommended to test for HCV recurrence or reinfection   Surveillance for hepatocellular carcinoma with twice-yearly ultrasound examination is recommended for patients with advanced fibrosis ( ie , Metavir stage F3 or F4) who achieve an SVR  

41. A baseline endoscopy is recommended to screen for varices if cirrhosis is present. Patients in whom varices are found should be treated and followed up as indicated   Assessment of other causes of liver disease is recommended for patients who develop persistently abnormal liver tests after achieving an SVR

42. Concomitant HBV infection For HBsAg + patients who are not already on HBV suppressive therapy, monitoring of HBV DNA levels during and immediately after DAA therapy for HCV is recommended and antiviral treatment for HBV should be given if treatment criteria for HBV are met

43. Liver transplantation Recommended for patients with end stage cirrhosis Chronic hepatitis C and alcoholic liver disease are the most common indications for liver transplantation, accounting for over 40% Recurrence of hepatitis C virus (HCV) following orthotopic liver transplantation (OLT) occurs in more than 95 percent of patients

44. PATIENTS WHO DEVELOP RECURRENT HCV INFECTION POST-LIVER TRANSPLANTATION Genotype 1 or 4 Infection in the Allograft, Including Those with Compensated Cirrhosis Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) with weight-based ribavirin for 12 or Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks Decompensated cirrhosis Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks

45. Genotype 2 or 3 Infection in the Allograft, Including Those with Compensated Cirrhosis Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks or Daily sofosbuvir (400 mg) and weight-based ribavirin for 24 weeks Decompensated cirrhosis Daily sofosbuvir (400 mg) and ribavirin (initial dose 600 mg/day, increased monthly by 200 mg/day as tolerated to weight-based dose) for 24 weeks