World Health Organization. Western Pacific Region

Transcription

1 Basic modules for HCV 1

2 HCV Module 1 Hepatitis C serological markers and virology 2

3 HCV Markers 3 Test Anti HCV (Anti hepatitis C virus antibody) HCV RNA (quantitative or qualitative) (Nucleic acid test) Clinical interpretation Indicates exposure to HCV Does not differentiate between active or resolved infections Remains positive even after successful treatment and clearance of HCV infection Cheap, easy, scalable A very good screening test for HCV infection Qualitative tests: HCV RNA is detectable (positive) or not Quantitative test: Amount of HCV RNA per unit blood Positive test indicates presence of active virus replication Becomes negative after successful HCV treatment Costly, time consuming and require expertise Differentiates between active and resolved infection Used for monitoring treatment and its efficacy

4 HCV Markers 4 Test HCV genotype HCVcAg (Hepatitis C core antigen) Clinical interpretation HCV has several strains which vary from each other genetically Classified based on genomic sequences into genotypes 1 to 6 Virus genotypes vary in sensitivity to some drugs Costly, needs specialized equipment and personnel Can help in deciding appropriate treatment in some situations No use if treatment does not depend on genotype A viral protein, produced only when virus is replicating Positive in unresolved chronic infection Become negative after successful HCV treatment Cheaper and easier than HCV RNA, should be scalable Reasonable and cheaper alternative of HCV RNA test However, may be negative in those with very low HCV RNA (lower sensitivity)

5 Interpretation of HCV serologic test results Anti HCV HCV RNA HCV Ag Interpretation Never infected /+ + + Recent infection Persistent (chronic) infection Previously infected (Infection resolved or cured) HCV antigen test gives the same information as HCV RNA. It has the potential to replace the RNA test currently not widely accepted, but is likely to do so in future 5

6 Testing strategy for chronic HCV infection 6

7 Summary A positive anti HCV test indicates exposure to HCV, which is either active or has resolved Anti HCV remains positive following successful treatment Anti HCV antibody test can be used as a screening test for HCV infection, and has been employed in several different strategies Tests for HCV RNA or HCVcAg serve as confirmatory test, indicate active infection and need for treatment. These are also useful to monitor treatment and confirm cure 7

8 Approaches for detecting HCV infection Mass screening (unselected testing of general population) Targeted screening Birth cohort testing Specific high risk groups Blood donor screening (primarily done for blood safety) 8

9 High risk groups for HCV infection The following group of people are at high risk for acquiring HCV infection People living with HIV Transfusion dependent (hemophilia, thalassemia) People who inject drugs Persons on maintenance hemodialysis High risk sexual practices (MSM, sex workers) 9

10 Who to test for chronic HCV infection Testing approach and population Focused testing in most affected populations General population testing Birth cohort testing Recommendations In all settings, serological testing for HCV antibody be offered to the following individuals Adults and adolescents from populations most affected by HCV infection Adults and children with a clinical suspicion of chronic viral hepatitis In settings with a 2% or 5% HCV antibody seroprevalence,all adults have access to and be offered HCV serological testing General population testing approaches should make use of existing community or facility based testing opportunities or programmes such as HIV or TB clinics, drug treatment services and antenatal clinics. This may be applied to specific identified birth cohorts of older persons at higher risk of infection and morbidity within populations that have an overall lower general prevalence 10 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P37

11 Initial assessment for chronic hepatitis B and C HBV HCV Chronic infection HBsAg Anti HCV Acute infection Anti HBc IgM HCV RNA, HCcAg etc. (without anti HCV antibody, excluding other hepatitis viruses) 11

12 How to test for chronic HCV infection 12 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P61

13 HCV Module 2 Extrahepatic manifestations of HCV 13

14 Extrahepatic manifestations HCV infection can lead to extrahepatic manifestations. Extrahepatic manifestations are likely to be affected by treatment. The prevalence of these extrahepatic manifestations is usually independent of the degree of liver fibrosis. Younossi et al

15 Prevalence of comorbidities among persons with HCV infection HCV infection can lead to extrahepatic manifestations. Among HCV infected persons, the three most common comorbidities are: depression (24%); diabetes mellitus (15%); and chronic renal disease (10%). The prevalence of these extrahepatic manifestations is usually independent of the degree of liver fibrosis. 15

16 Cryoglobulinemia One of the most common disorders associated with hepatitis C. A blood disorder caused by cryoglobulins deposited in the small and medium sized blood vessels. Many people are not symptomatic. Affect the skin, kidneys, nerves and joints. 16

17 Depression The various factors contribute to depression. The origins of depression with HCV are most likely a combination of: physiological characteristics of the virus; emotional and physical health of the individual; the extent of a person s social support network; personal beliefs; and available treatment options. 17

18 Diabetes HCV can induce insulin resistance. Curing HCV has been found to improve blood sugar levels. 18

19 Sjogren s Syndrome An autoimmune disease that affects the eyes and mouth, making them dry. Although HCV has not been directly linked to Sjogren s syndrome, it is found more often in people with hepatitis C than in the general population. 19

20 Chronic Renal Disease HCV infection is both a cause and a complication of chronic kidney disease, occurring largely in the context of cryoglobulinemia. Type I membrano proliferative glomerulonephritis associated with cryoglobulinemia is the most common form of kidney disease associated with HCV infection. 20

21 HCV Module 3 Hepatitis C transmission and prevention 21

22 Transmission routes of HCV Health care associated Blood products Unsafe injections Medical procedure (i.e. Needle stick injury) Sexual (HIV positive, men who have sex with men) Vertical: Mother to child (4 8%) Horizontal: Young children, household contacts Persons who inject drugs (PWID) 22

23 Needle stick injury (NSI) The risk of infection due to NSI ~40% 3~10% 0.2~0.5% 23 Alter HJ, Seeff LB, Kaplan PM, McAuliffe VJ, Wright EG, et al. Type B hepatitis: the infectivity of blood positive for e antigen and DNA polymerase after accidental needlestick exposure. N Engl J Med 1976;295: Alter MJ. Occupational exposure to hepatitis C virus: a dilenma. Infect Control Hosp Epidemiol 1994;15: Artenstein AW, Hicks GB, Goodwin BS Jr., Hilliard JK, Human infection with B virus following a needle stick injury Rev Infec Dis 1991;13: Gerberding JL, Bryant LeBlanc CE, Nelson K, Moss AR, Osmond D, et al. Risk of transmitting the human immunodeficiency virus, cytomegalovirus, and hepatitis B virus to health care workers exposed to patients with AIDS and AIDS related conditions. J Infect Dis 1987;156:1 8.

24 Prevention of HCV transmission Primary prevention No vaccine for hepatitis C Reducing the risk of exposure to the virus in health care setting and higher risk population Seconodary and tertiary prevention Education and counselling on option for care Immunization with Hep A & B vaccines Early and appropriate medical management Regular monitoring for early diagnosis 24

25 Prevention of HCV transmission WHO guidance in health care settings Hand hygiene: including surgical hand preparation, hand washing and use of gloves Safe handling and disposal of sharps and waste Safe cleaning of equipment Testing of donated blood Improved access to safe blood Training of health personnel 25

26 Prevention of HCV transmission WHO recommendations for people who inject drugs Offer people who inject drugs the rapid hepatitis B vaccination regimen Offer people who inject drugs incentives to increase uptake and complete the hepatitis B vaccination Implement sterile needle and syringe programmes that also provide low dead space syringes for distribution to people who inject drugs Offer peer interventions to people who inject drugs to reduce the incidence of viral hepatitis Offer opioid substitution therapy to treat opioid dependence, reduce HCV risk behavior and transmission through injecting drug use, and increase adherence to HCV treatment Integrate the treatment of opioid dependence with medical services for hepatitis 26

27 HCV Module 4 Natural history of Hepatitis C 27

28 Acquisition of HCV infection Usual routes of transmission of HCV infection are: Blood transfusion Unsafe injection practices Healthcare related Injection drug use Nosocomial Unsterile surgical procedures, hemodialysis, tissue transplant Body piercing, tattooing Sexual activity Mother to child 28

29 Natural history of HCV infection Acute HCV infection Resolved infection 15 45% (~25%) Persistent infection 55 85% (~75%) Defined as persistence of HCV for >6 months (this time cut off is arbitrary but well accepted) 29

30 Acute HCV Incubation period: 6 weeks to 6 months Variable manifestations Asymptomatic Mild non specific symptoms Mild clinical jaundice in up to 15% of patients Serum aminotransferase (ALT, AST) levels may be high (up to 10 times upper reference limit) Usually goes unrecognized May be identified in those on high risk and on regular monitoring for HCV infection (e.g. persons on maintenance hemodialysis) 30

31 Diagnosis difficult Acute HCV infection A person with HCV infection and one of the following: Recent change in anti HCV antibody/hcv RNA status (from ve to +ve) Recent jaundice or ALT >10 x ULN (beginning <20 wk ago) J Hepatol 2012; 57:

32 Natural history following acute HCV Persistent or chronic infection A person who continues to have detectable HCV RNA in blood beyond six months after acute infection Resolved infection HCV disappears from the body within 6 months after infection However, anti HCV usually continues to be positive Relapse is rare once RNA is spontaneously cleared Re infection can occur following repeat exposure (e.g. in those who continue to be at high risk: IDU, dialysis) 32

33 Definition HCV infection: Active vs resolved Active = Virus is still present in the host Resolved = No virus in the host (immune system has cleared the infection) Laboratory diagnosis Active = Serum HCV RNA +ve Resolved = Serum HCV RNA ve 33

34 Natural history of HCV infection Acute HCV infection Resolved infection 15 45% (~25%) Persistent infection 55 85% (~75%) Anti HCV HCV RNA +ve ve Anti HCV HCV RNA +ve +ve 34

35 Natural history of HCV infection Infection persistent ~0.3%/year Chronic hepatitis with mild fibrosis ~3%/year Chronic hepatitis with severe fibrosis Liver cirrhosis (~20% in 20 years) ~3%/year ~5%/year Liver cirrhosis (decompensated) Hepatocellular carcinoma Death 35

36 Natural history of chronic hepatitis C Chronic infection leads to long term inflammation Results in fibrosis or scarring Metavir fibrosis stage Fibrosis Nodular regeneration Distortion of architecture Develops in ~20% over a year period 36

37 Prolonged liver injury leads to scarring (fibrosis) Central vein F1 F2 Portal tract F3 F4 Scarring/fibrosis: particularly affect the central vein and portal tracts (blood vessels) 37

38 Summary HCV infection can be either acute or persistent Acute HCV infection usually goes unnoticed A proportion of those with HCV infection clear the virus spontaneously Among those with chronic HCV infection, ~20% develop cirrhosis over years Among those with HCV cirrhosis, ~3% develop HCC every year 38

39 Module review What serological markers are necessary to diagnose acute hepatitis C? What should we assess for the patients with anti HCV antibody positive next? What are the goal and surrogate endpoints of antiviral therapy for chronic HCV infection? Who is candidate for treatment for chronic HCV infection? 39

40 HBV Module 5 Assessment of liver fibrosis 40

41 METAVIR stage Definition No fibrosis Portal fibrosis without septa Liver biopsy METAVIR liver biopsy scoring system F0 F1 F2 F3 F4 Portal fibrosis with septa Numerous septa without cirrhosis Cirrhosis 41 GUIDELINES FOR THE SCREENING, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS C INFECTION UPDATED VERSION (WHO 2016)

42 Clinical features Indirect tests Diagnosis of cirrhosis Hemogram, especially platelet count Biochemical tests: ALT, AST, albumin Composite measures Imaging FIB 4, APRI, Fibrotest Ultrasound Specialized tests Endoscopy for varices Liver stiffness (elastography) 42

43 Assessing the degree of liver fibrosis Non invasive tests Components Requirements Cost APRI AST, platelets Simple serum and FIB 4 Age, AST, ALT, Platelets hematology test FibroTest ggt, haptoglobin, bilirubin, A1apoprotein, α2 macroglobulin AST; aspartate aminotransferase ALT; alanine aminotransferase APRI; aspartate aminotransferase to platelet ratio index FIB 4; fibrosis 4 score Specialized tests at designed laboratories Fibroscan Transient elastography Dedicated equipment +++ Fibroscan (http.myliverexam.com/en/lexamen fibroscan.html) GUIDELINES FOR THE SCREENING, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS C INFECTION UPDATED VERSION (WHO 2016)

44 AST Platelet Ratio Index (APRI) AST upper limit of normal: Use 40 IU/L if none specified Platelet count: expressed in terms of X1000/microlitre 44

45 FIB 4 AST/ALT upper limit of normal: Use 40 IU/L if none specified Platelet count: expressed in terms of X1000/microlitre Calculation needs a calculator, a phone App or an online tool 45

46 Cirrhosis versus no cirrhosis 46

47 Cirrhosis versus no cirrhosis In resource constraint settings, two cut off values help in treatment prioritization Values above the high cut off High probability of cirrhosis Values between the lower cut off High certainty that there is no cirrhosis Between the two cut offs Cirrhosis possible but not very certain 47

48 Transient elastography (Fibroscan) 48

49 Transient elastography (Fibroscan) Transducer sends a mechanical shearwave Monitor display of Fibroscan Large explored volume (at least 100 times more than biopsy) 49

50 Transient elastography (Fibroscan) Median Calculated from 10 valid measurement Is used as the final result Inter quartile range (IQR) Spread of the middle half of observations Should be small IQR/median Ratio of IQR to median Indicates variability in different reading High values means large variation If > 30%, implies no reliability 50

51 Fibroscan For liver stiffness measured by transient elastography, several different cut offs have been proposed in different studies and disease conditions A commonly used cut off for cirrhosis: >12.5 kpa 51

52 Fibroscan Advantages Easy, non invasive Can be done in outpatient or community settings Takes <10 minutes to perform Health care staff can be easily trained Limiting factors High cost of equipment Equipment needs regular maintenance/calibration by trained personnel No universal cut off values for specific stages of fibrosis Difficult to measure in very obese 52

53 HCV Module 6 Treatment for Chronic Hepatitis C 53

54 Why treat HCV infection? Delay the progression of cirrhosis Reduce the incidence of hepatocellular carcinoma Improve quality of life Improve long term survival (reduce death) Potentially, reduce transmission 54

55 Effect of treatment on natural history Chronic HCV, no cirrhosis Halts progression of fibrosis Marked reduction in risk of progression to cirrhosis Marked reduction in risk of HCC? Reversal of fibrosis Chronic HCV with cirrhosis Reduced risk for HCC Reduced risk of decompensation? Reversal of cirrhosis in early stages 55

56 Clinical management of HCV infection 1. Natural history of HCV infection 2. Clinical assessment of persons with chronic hepatitis C 3. Extrahepatic manifestation of HCV 4. Why to treat for HCV 5. Who to treat for HCV 6. How to treat for HCV 7. How to monitor during treatment for HCV 56

57 57

58 Who should be treated for HCV infection? 58

59 Who should be treated for HCV infection? All patients ( 12 years of age) with detectable HCV RNA (Drugs are currently not approved for use at age <12 y) (Also, only some drugs are approved in y age group) 59

60 Clinical management of HCV infection 1. Natural history of HCV infection 2. Clinical assessment of persons with chronic hepatitis C 3. Extrahepatic manifestation of HCV 4. Why to treat for HCV 5. Who to treat for HCV 6. How to treat for HCV 7. How to monitor during treatment for HCV 60

61 Considerations for treatment 61

62 Direct acting Anti viral Drugs (DAAs) DAAs = Drugs that specifically act against hepatitis C virus Three groups depending on mechanism of action NS3 protease inhibitors (.previr) simeprevir NS5B inhibitors (.buvir) sofosbuvir NS5A inhibitors (.asvir) daclatasvir 62

63 HCV infection: Common treatment regimens Interferon based Not recommended Pegylated Interferon plus ribavirin Pegylated interferon plus ribavirin plus sofosbuvir Interferon free, DAA based treatment Recommended NS5B inhibitor (e.g, sofosbuvir/dasabuvir) + NS3 inhibitor (e.g, Glecaprevir) NS5A inhibitor (e.g, ledipasvir/daclatasvir) Both of the above 63

64 DAA regimens as per WHO Guidelines Fixed dose combinations Sofosbuvir + Ledipasvir Sofosbuvir + Velpatasvir Sofosbuvir + Daclatasvir (also separately) Other drugs Ribavirin (in combination with DAA) 64

65 Treatment regimens for HCV infection: WHO Choice of HCV treatment regimen depends on Patient s age Virus genotype Genotype dependent regimens Pan genotypic regimens Cirrhosis or no cirrhosis 65

66 Drug interactions/ Warnings with DAA use Drugs Sofosbuvir (SOF) Daclatasvir (DCV) Ribavirin (RBV) Contraindication / warning Amiodarone co administration Renal failure (egfr < 30 ml/min/1.73m 2 ) Drugs that induce or inhibit activity of CYP3A Pregnancy or unwillingness to use contraception, breastfeeding Severe concurrent medical disease (cardiac failure, COPD) Co administration of didanosine 66

67 General rules for DAA based treatment Genotype 1, 4, 5 and 6 Similar treatment 2 Easy to treat 3 Difficult to treat If cirrhosis present Longer duration (24 weeks) of treatment Addition of ribavirin may provide additional benefit Higher response rate Shorter duration Higher risk of complications and need for monitoring during Rx Higher risk of relapse 67

68 Approach to treatment Anti-HCV +ve HCV RNA test HCV RNA -ve HCV RNA +ve No treatment or follow-up Age years Age 18 years Genotype-specific regimen Pan-genotype regimen 68

69 Approach to treatment in adults Anti HCV +ve, HCV RNA +ve Age >18 years Look for cirrhosis (APRI) No cirrhosis Pan genotypic regimens Cirrhosis Sofosbuvir + velpatasvir 12 weeks Sofosbuvir + velpatasvir 12 weeks Sofosbuvir + daclatasvir 12 weeks Sofosbuvir + daclatasvir 24 weeks Glecaprevir + pibrentasvir 8 weeks Glecaprevir + pibrentasvir 12 weeks Sofosbuvir + daclatasvir 12 weeks * *if the prevalence of genotype 3 is <5% Sofosbuvir + velpatasvir X 12 weeks works both with and without cirrhosis, but may be costlier than other drugs 69

70 Summary of treatment 70

71 Treatment in children and adolescents Anti-HCV +ve, HCV RNA +ve Age y / weight 35 Kg HCV genotype Genotype 2 Genotype 3 Genotype 1, 4, 5 or 6 Sofosbuvir/ribavirin 12 wk Sofosbuvir/ribavirin 24 wk Sofosbuvir/ledipasvir 12 wk 71 Sofosbuvir, ledipasvir and ribavirin are the only drugs approved for use in y age group

72 Pre treatment Assessment Clinical features Laboratory Fibrosis/cirrhosis HCV RNA HCV genotype Cirrhosis Decompensation Hemogram Liver function tests Creatinine Non invasive fibrosis assessment Fibroscan: if available UGI endoscopy, if needed Only if age years 72

73 Outcome of interest Sustained virological response at 12 weeks posttreatment (SVR12) Undetectable HCV RNA at 12 weeks after stopping drugs No cirrhosis ~95 98% Cirrhosis ~80 90% 73

74 HCV Module 7 Monitoring for Chronic Hepatitis C 74

75 75

76 Monitoring While on treatment: All patients Adherence, toxicities Hemoglobin, TLC, platelets (only with IFN or RBV) Liver function tests (esp. if cirrhosis) Creatinine 12 weeks after completion of treatment: All patients Treatment response: HCV RNA (12 weeks after completion) On follow up after SVR: Only in those with cirrhosis Hepatocellular carcinoma Portal hypertension 76

77 Monitoring on HCV treatment 77