APPROACH TO VIRAL HEPATITIS in children.pptx

APPROACH TO VIRAL HEPATITIS
BY: DR. RAHEEL AHMED
HEPATITIS
Inflammation of liver parenchyma

2 types:
Acute – duration < 6 months
Chronic – duration ≥ 6 months

It’s commonly caused by a viral infection, but there are other possible causes of hepatitis. These include autoimmune hepatitis and hepatitis that occurs as a secondary result of medications, drugs, toxins, and alcohol.
Etiology
Viral • Hepatotropic viruses – HAV, HBV , HCV, HDV, HEV, non A-E Viruses
Non hepatotropic viruses (cause hepatitis as a component of multisystem disease) – CMV, EBV, VZV, HSV, HIV, Rubella, Adenovirus, Enteroviruses, parvovirus B-19, arbovirus, paramyxovirus, coxsackievirus etc.
Non viral Hepatitis – Leptospirosis, Enteric fever, TB, Histoplasmosis, Amebiasis, abscess, bacterial sepsis, fitz-hugh Curtis syndrome, brucellosis
Drug and toxin induced – Acetaminophen, Phenytoin, INH, Nitrofurantoin, Methotrexate, Alcohol.
Autoimmune - Autoimmune hepatitis, SLE, JRA, sclerosing cholangitis
Metabolic – Tyrosinemia, Wilson disease, alpha 1 antitrypsin deficiency
Anatomic causes – Biliary atresia, Choledochal cyst
Ischaemic hepatitis – Shock, CHF, Budd Chiari syndrome
Non alcoholic fatty liver disease – idiopathic, Reye syndrome
VIRAL HEPATITIS
Features of Hepatotropic Viruses
Pathogenesis
The viruses do not directly cause apoptosis. Rather, infection of liver cells activates the innate and adaptive immune system leading to an inflammatory response which causes cellular damage and death.
Depending on the strength of the immune response, the types of immune cells involved and the ability of the virus to evade the body's defense, infection can either lead to clearance (acute disease) or persistence (chronic disease) of the virus.
The acute response of the liver to hepatotropic viruses involves a direct cytopathic and an immune mediated injury. Entire liver is involved n necrosis is mostly marked in centrilobular areas
With recovery, the liver morphology returns to normal within 3 months.
The chronic presence of the virus within liver cells results in multiple waves of inflammation, injury and wound healing that overtime lead to scarring or fibrosis and culminate in HCC
In chronic case, inflammatory infiltrate settles in periportal areas and leads to progressive scarring – HBV, HCV
Biochemical Profiles in Acute Infectious Phase
As a reflection of Cytopathic injury
Increased AST/ALT.
Rapidly falling AST/ALT predict poor outcome.
Cholestasis
Elevated conjugated billirubin
Elevated ALP, 5’ nucleotidase, Urobilinogen, GGT
3.Altered Synthetic functions
Hypoalbuminaemia,
Prolonged PT/INR
Metabolic disturbance (Hypoglycemia, lactic acidosis, hyperammonemia)
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E

1. APPROACH TO VIRAL HEPATITIS BY: DR. RAHEEL AHMED

2. Pretest Questions No parenteral transmission occur in the following hepatotropic viruses HAV HBV HCV HDV HEV HBV is present in high concentrations in serous exudates saliva vaginal fluid semen urine

3. Pretest Questions Risk factors for HBV infection in children and adolescents include acquisition by the following EXCEPT intravenous drug contaminated needles sexual contact intimate contact with carriers sharing toys Routine screening for HBV infection requires assay of multiple serologic markers, all the following are true EXCEPT HBsAg is the first serologic marker of infection to appear Anti- HBc is a valuable serologic marker of acute HBV infection anti-HBs and anti- HBc are detected in persons immunized with hepatitis B vaccine HBeAg is a marker of infectivity HBsAg levels fall before symptoms wane

4. Pretest Questions The disease exists in short-term (acute) and long-term (chronic) forms. How long does acute hepatitis last? Less than 6 months Less than 3 months About 6 weeks 1 month Regarding epidemiology of HBV, the following are true EXCEPT intrauterine infection occurs in 2.5% B . antigenemia appear 1-3 mo after birth C . HBsAg is inconsistently recovered in human milk of infected mothers D . breastfeeding of nonimmunized infants by infected mothers confer a greater risk of hepatitis E . HBV has 8 genotypes (A-H)

5. HEPATITIS Inflammation of liver parenchyma 2 types: Acute – duration < 6 months Chronic – duration ≥ 6 months It’s commonly caused by a viral infection, but there are other possible causes of hepatitis. These include autoimmune hepatitis and hepatitis that occurs as a secondary result of medications, drugs, toxins, and alcohol.

6. Etiology Viral • Hepatotropic viruses – HAV, HBV , HCV, HDV, HEV, non A-E Viruses Non hepatotropic viruses (cause hepatitis as a component of multisystem disease) – CMV, EBV, VZV, HSV, HIV, Rubella, Adenovirus, Enteroviruses, parvovirus B-19, arbovirus, paramyxovirus, coxsackievirus etc. Non viral Hepatitis – Leptospirosis, Enteric fever, TB, Histoplasmosis, Amebiasis , abscess, bacterial sepsis, fitz-hugh Curtis syndrome, brucellosis Drug and toxin induced – Acetaminophen, Phenytoin, INH, Nitrofurantoin, Methotrexate, Alcohol. Autoimmune - Autoimmune hepatitis, SLE, JRA, sclerosing cholangitis Metabolic – Tyrosinemia , Wilson disease, alpha 1 antitrypsin deficiency Anatomic causes – Biliary atresia, Choledochal cyst Ischaemic hepatitis – Shock, CHF, Budd Chiari syndrome Non alcoholic fatty liver disease – idiopathic, Reye syndrome

7. VIRAL HEPATITIS

8. Features of H epatotropic Viruses

9. Pathogenesis The viruses do not directly cause apoptosis. Rather, infection of liver cells activates the innate and adaptive immune system leading to an inflammatory response which causes cellular damage and death . Depending on the strength of the immune response, the types of immune cells involved and the ability of the virus to evade the body's defense, infection can either lead to clearance (acute disease) or persistence (chronic disease) of the virus. The acute response of the liver to hepatotropic viruses involves a direct cytopathic and an immune mediated injury. Entire liver is involved n necrosis is mostly marked in centrilobular areas With recovery, the liver morphology returns to normal within 3 months . The chronic presence of the virus within liver cells results in multiple waves of inflammation, injury and wound healing that overtime lead to scarring or fibrosis and culminate in HCC In chronic case, inflammatory infiltrate settles in periportal areas and leads to progressive scarring – HBV, HCV

10. Biochemical Profiles in Acute Infectious Phase As a reflection of Cytopathic injury Increased AST/ALT. Rapidly falling AST/ALT predict poor outcome. Cholestasis Elevated conjugated billirubin Elevated ALP, 5’ nucleotidase , Urobilinogen, GGT 3.Altered Synthetic functions Hypoalbuminaemia , Prolonged PT/INR Metabolic disturbance (Hypoglycemia, lactic acidosis, hyperammonemia )

11. Hepatitis A Most prevalent (developing countries) HAV – RNA virus, picornavirus family Host – human and other primates Transmission – Faeco oral route ,rarely perinatal Mean incubation period: 3 weeks Faecal excretion of virus starts late in the incubation period and reaches the peak just before the onset of symptoms and resolves within 2 weeks after onset of jaundice

12. CLINICAL FEATURES Acute hepatitis only In young children mostly asymptomatic or cause anicteric illness Illness is usually symptomatic in older children n adults, with underlying liver disease n immunocompromised Acute febrile illness with abrupt onset of anorexia, malaise , vomiting, jaundice Duration is usually 7-14 days Hepatomegaly , regional lymph nodes and spleen may be enlarged Acute pancreatitis, gastrointestinal ulcers , myocarditis, nephritis, arthritis, leukocytoclastic vasculitis, cryoglobulinemia – circulating immune complexes

13. DIAGNOSIS Detection of Anti-HAV Ig M antibodies – symptoms are apparent, remains for 4-6 months after acute infection Viral particles in faeces Ig G type is detected within 8 weeks of infection (confers long term protection) Rise in serum transaminases, bilirubin and alkaline phosphatase is universal and hence cannot distinguish between other forms of hepatitis

14. COMPLICATIONS No specific treatment (only supportive treatment hydration Antipyretics, analgesics & antiemetics ) Fat soluble vitamins and antipruritic agents for prolonged cholestatic form. Serial monitoring for signs of ALF, hepatic encephalopathy (flapping tremors, altered sleep pattern, excessive irritability, inconsolable cry), Prolongation of PT No role for vitamin k, appetizers, antibiotics, bed rest n dietry restriction of fat, milk, turmeric, pickles, spices Treatment Most patients – full recovery Acute liver failure – rare. Seen in immunocompromised and those with underlying liver disorders Prolonged cholestatic syndrome - persistent hyperbilirubinemia, pruritus, fat malabsorbtion and constitutional symptoms that last for 12-16 weeks in the absence of biliary obstruction on sonograms.

15. Prevention Patients contagious 2 weeks before and 7 days after onset of jaundice. Handwashing after toilet, before meal Pre exposure prophylaxis’ for travelers to endemic regions: Immunoglobulins only: Travelers who elect not to receive hepatitis A vaccine Age <12 months A llergic to a component of hepatitis A vaccine IGG plus Vaccine: For travel that will begin in ≤2 weeks O lder adults, immunocompromised persons, and persons with chronic liver disease or other chronic medical conditions

16. Post exposure prophylaxis of household n institutional Hep A contacts Immunoglobulins A ge <12 months Age >40 years I mmunocompromised persons OR who have chronic liver disease vaccine is contraindicated. Vaccine : Healthy persons b/w 12 months n 40 years Recommended doses of IG for pre exposure prophylaxis Up to 1 month: 0.1 mL/kg Up to 2 months: 0.2 mL/kg 2 months or longer: repeat dose of 0.2 mL/kg every 2 months . F or post exposure prophylaxis 0.1 mL/kg

17. HAV vaccine Inactivated vaccine ( Haverix ) Dose: 0.5 ml I.M in deltoid 2 doses schedule 1 st dose after 12 months age n 2 nd dose 6-12 months after 1 st dose

18. Counselling Parents should be counselled about Benign nature of illness Likelihood of complete natural recovery. Avoidance of restrictions on physical activity & diet. Lack of role for drugs. Hygienic measures Prognosis Excellent prognosis with no long term sequale

19. Hepatitis B DNA virus, Hepadnaviridae family. Discovered in 1966. Also known as Dane Particle. Incubation period: 45-160 days , mean: 120 days HBV has 10 genotypes (A-J) HBV is present in high concentrations in blood , serum and serous exudates and m oderate concentrations in semen, vaginal fluid and saliva

20. Modes of Transmission: Perinatal – Vertical transmission from mother to baby Parenteral – Transfusion of infected blood and its products, using non sterile syringes, needles for acupuncture, tattoos and medical instruments. Sexual • Risk of transmission increases with the level of HBV DNA in serum and HBeAg positive No risk factor is identified in 40% cases HBV is not spread by sharing utensils, breastfeeding, hugging

21. Modes of Transmission: In children, most important mode is vertical transmission. Risk is greatest if mother is HbeAg + ve n prior infant developed HBV despite of prophylaxis 90% of these infants remain chronically infected if untreated Serological markers appear 1-3 months after birth Intrauterine infection occurs in 2.5 % HBsAg is inconsistently recovered from human milk of infected mothers. Breastfeeding of non immunized infant by an infected mother does not confer a greater risk of hepatitis than formula feeding.

22. CLINICAL FEATURES: Clinicopathologic syndromes include the following: Acute hepatitis with resolution: (symptoms persists for 6-8 weeks) Chronic hepatitis, with or without progression to cirrhosis or HCC– depends upon age at infection Fulminant hepatitis with massive liver necrosis Coinfection/Superinfection with hepatitis D virus

23. CLINICAL FEATURES: Many acute cases – Asymptomatic Acute symptomatic similar to HAV and HCV, but more severe n can involve skin n joints Fatigue, anorexia, malaise, jaundice, Dark urine, clay-colored or light stools, and abdominal pain Tender hepatomegaly Splenomegaly in 15 -20% cases A few spider angiomas may appear during the icteric phase and disappear during convalescence

24. Extrahepatic M enifestations Papular acrodermatitis Gianotti - crosti syndrome Polyarteritis Nodosa Glomerulonephritis Aplastic anemia In few, illness preceeded by serum sickness like prodrome – arthralgia, skin lesions including urticarial, purpural or maculopapular rash.

25. DIAGNOSIS:

26. DIAGNOSIS: Definitive diagnosis depends on serologic testing for HBV infection. Routine screening requires- HBsAg , anti- HBc , anti-HBs HBsAg (also known as the Australia antigen) -early serological marker of infection. Its presence indicates current hepatitis B infection. Persistence of HBsAg beyond 6 months- chronic infection Anti-HBs – serologic recovery n protection HBeAg – marker of infectivity Anti- HBc – IGM (acute infection), IGG ( chronic nfection ) HBV DNA – active replication LFT’s - Elevations of ALT and AST levels are hallmarks of acute hepatitis. Values as high as 1000-2000 IU/L are typical, with ALT values higher than AST values. The prothrombin time is the best indicator of prognosis

27. Serological Diagnosis in Hepatitis B

28. Histological markers Liver biopsy : invasive procedure, which is indicated only when a specific diagnosis of CHB cannot be posed or excluded using non-invasive procedures liver biopsy - extent of histologic involvement and response to therapeutic protocols. Pathognomonic ground glass hepatocyte inclusions Transient elastometry ( FibroScan )- rapid, easy to perform, reproducible, non-invasive technique for the evaluation of liver stiffness

29. APRI (AST to PLt Ratio Index) SCORE For detection of cirrhosis, using an APRI cutoff score of 2.0 was more specific (91%) but less sensitive (46 %). Lower the APRI score (less than 0.5) – rule out cirrhosis

30. Initial evaluation of patients History and physical examination Family History of liver disease, HCC Laboratory tests to assess liver disease Tests for HBV replication— HBeAg /anti- HBe , HBV DNA. Tests to rule out viral co-infections—anti-HCV, anti-HDV, and anti-HIV in those at risk. Tests to screen for HCC–AFP at baseline and, in high risk patients-Ultrasound (USG ). Consider liver biopsy to grade and stage liver disease - for patients who meet criteria for chronic hepatitis

31. Treatment of Acute HBV Acute HBV – largely supportive , Care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids Avoidance of unnecessary medications. Acetaminophen/Paracetamol and medication against vomiting should not be given. Close monitoring for ALF

32. Goals of treatment Chronic Hepatitis B Suppression of HBV replication to undetectable levels Seroconversion (development of anti- HBe Decrease hepatic necroinflammation and fibrosis Prevent progression to cirrhosis, liver failure and HCC Treatment indicated for those with immune active form (elevated ALT >2times upper limit of normal and/or AST), who have fibrosis on liver biosy Immune tolerant patients – those with normal ALT, AST, HbeAg positive with elevated viral load - monitor Indication of treatment Chronic Hepatitis B

33. Treatment Recommendations in chronic Hep B Who to treat: As a priority, all adults, adolescents and children with CHB and clinical evidence of compensated or decompensated cirrhosis (APRI score >2) should be treated, regardless of ALT levels, HBeAg status or HBV DNA levels Treatment is recommended for adults with CHB who do not have clinical evidence of cirrhosis ( APRI score <2) but are aged more than 30 years (in particular), and have persistently abnormal ALT levels and evidence of high-level HBV replication (HBV DNA >20 000 IU/mL), regardless of HBeAg status In HBV/HIV- coinfected individuals, ART should be initiated in all those with evidence of severe chronic liver disease, regardless of CD4 count; and in all those with a CD4 count ≤500 cells/mm3, regardless of stage of liver disease

34. Who not to treat but continue to monitor Persons without clinical evidence of cirrhosis ( APRI score <2) , and with persistently normal ALT levels and low levels of HBV replication (HBV DNA <2000 IU/mL), regardless of HBeAg status or age Continued monitoring is necessary in all persons with CHB, to determine if antiviral therapy may be indicated in the future to prevent progressive liver disease. These include: Persons without cirrhosis aged 30 years or less, with HBV DNA levels >20 000 IU/ mL but persistently normal ALT HBeAg -negative persons without cirrhosis aged 30 years or less, with HBV DNA levels that fluctuate between 2000 and 20 000 IU/mL, or who have intermittently abnormal ALT levels

35. Orals vs. IFN A dvantage of NA therapy few side-effects and a one-pill-a-day oral administration . Disadvantage of NA – resistence n slight risk of nephropathy with ( adefovir , tenofovir ) Advantages of IFN - absence of resistance, and achievement of higher rates of HBeAg and HBsAg loss Disadvantages of IFN - less than 50% of persons treated will respond, its high cost, treatment duration of 24weeks,administration by SC injection and common side-effects (flu like symptoms, marrow suppression, depression, retinal changes, autoimmune disorders) n frequent monitoring limited its use Relative and absolute contraindications to IFN - presence of decompensated cirrhosis and hypersplenism , thyroid disease, autoimmune diseases, severe coronary artery disease, renal transplant disease, pregnancy, seizures and psychiatric illness, concomitant use of certain drugs, retinopathy, thrombocytopenia and leucopenia IFN also cannot be used in infants less than 1 year, older than 60y and in pregnant women

36. Nucleotide/nucleoside Analogues Lamivudine (inhibits viral enzyme reverse transcriptase) Use: In children >2y Its use for 52 weeks – HBeAg clearance in 34% patients Duration of treatment - >6months after viral clearance Entecavir Use: In children > 2y Rate of seroconversion 23 % Adefovir Use: >12 years Rate of seroconversion 23% Tenofovir Use: >12 years Rate of seroconversion 23 %

37. Monitoring Monitoring for disease progression and treatment response: ALT levels (and AST for APRI), HBsAg , HBeAg , and HBV DNA levels Non-invasive tests (APRI score or FibroScan ) to assess for the presence of cirrhosis, in those without cirrhosis at baseline If on treatment, adherence should be monitored regularly and at each visit

38. Monitoring for tenofovir and entecavir toxicity Measurement of baseline renal function and assessment of baseline risk for renal dysfunction should be considered in all persons prior to initiation of antiviral therapy . Renal function should be monitored annually in persons on long-term tenofovir or entecavir therapy, and growth monitored carefully in children

39. More frequent monitoring (at least every 3 months for the first year) In persons who do not yet meet the criteria for antiviral therapy Persons with more advanced disease (compensated or decompensated cirrhosis ) During the first year of treatment to assess treatment response and adherence Where treatment adherence is a concern In HIV- coinfected persons; and in persons after discontinuation of treatment :

40. Monitoring for hepatocellular carcinoma ( HCC) Routine abdominal ultrasound and alpha-fetoprotein testing every six months: Persons with cirrhosis, regardless of age or other risk factors Persons with a family history of HCC Persons aged over 40 years without clinical evidence of cirrhosis, and with HBV DNA level >2000 IU/mL

41. WHO Recommendations: when to stop treatment Lifelong NA therapy All persons with cirrhosis ( or APRI score >2 in adults) require lifelong treatment with nucleos (t)ide analogues (NAs), because of the risk of reactivation. Discontinuation : Persons without clinical evidence of cirrhosis (APRI score ≤2 in adults ) Who can be followed long term for reactivation Evidence of HBeAg loss and seroconversion to anti- HBe (in persons initially HBeAg -positive) and after completion of at least one additional year of treatment Persistently normal ALT levels and persistently undetectable HBV DNA levels. Retreatment: Retreatment is recommended if there are consistent signs of reactivation ( HBsAg or HBeAg becomes positive, ALT levels increase, or HBV DNA becomes detectable again)

42. HBV/HDV coinfection There are limited data on definitive guidance on the management of persons with HDV infection PEG-IFN is the only drug effective against HDV; antiviral NAs have no or limited effect on HDV replication Optimal duration of therapy is not well defined More than 1 year of therapy may be necessary Most patients relapse after discontinuation of therapy

43. HBV/HIV coinfection HBV DNA levels are usually low or undetectable and as HCV is responsible for the activity of chronic hepatitis in most persons Patients should generally receive initial treatment for HCV infection The optimal regimens are uncertain, and more treatment studies are required in coinfected persons . PEG-IFN and ribavirin can be effective HBV DNA monitoring is necessary as there is a potential risk of HBV reactivation during treatment or after cleIrance of HCV, which can be treated with NAs HBV/HCV coinfection In HBV/HIV- coinfected adults, adolescents and children aged 3 years or older, tenofovir + lamivudine (or emtricitabine ) + efavirenz as a fixed-dose combination is recommended

44. Extrahepatic manifestations Comparative trials of antiviral therapy are lacking, and the efficacy reported in case reports is variable. Lamivudine has been the most widely used, and entecavir and tenofovir would be expected to have enhanced efficacy in this group. PEG-IFN may worsen some immune-mediated extrahepatic manifestations and it is advisable to avoid its use.

45. PREVENTION: Screening of pregnant women Use of HBIG and HBV vaccine infants Mothers with HBV DNA load > 200,000 IU/ml – telbivudine , lamivudine or tenofovir during 3rd trimester should be given. ( Tenofovir is preferred, IFN is contraindicated) Infants born to HBsAg positive mothers – 0.5 ml HBIG within 12 hours of birth along with 1st dose of HBV vaccine Vaccine – Recombinant vaccine 0.5 ml given IM on anterolateral thigh at birth, then 6 weeks, 6 months Routine vaccination of previously unvaccinated children aged <19y

46. PREVENTION If mother’s status is not known, vaccine should be administered regardless of birth weight within 12 hours of birth Infants < 2000g , HBIG and HBV should be given Mother’s HBsAg status should be identified and if she is positive and the infant is > 2000g, HBIG should be given no later than 1 week Post vaccination testing for HbsAg – 9-18 months. If positive for anti HBs , then the child is immune to HBV If result is positive for HBs Ag only – paediatric gastroenterologist If negative for both – second complete HBV vaccine series Administration of 4 doses of vaccine is permissible when combination vaccines are used after birth dose

47. PREVENTION: Exposure following intimate or identifiable blood exposure : HBIG + HBV at exposure, then HBV at 1, 6 months Household contancts – HBV vaccine at exposure, 1,6 months. Same dose as above Immunocompromised – 40 microgram Recombivax at exposure, 1 , 6 months along with HBIG at exposure

48. COMPLICATIONS: Acute liver failure with coagulopathy, encephalopathy and cerebral edema ( more in superinfection with HDV) n immunocompromised host Chronic hepatits may lead to cirrhosis and end stage liver disease complications and Hepatocellular carcinoma Membrano – glomerular nephritis – deposition of complement and HBeAg in the glomerulus Prognosis: In general, outcome is favourable Mortality from ALF is 30% Age at infection: infection acquired perinatally : Poor prognosis Adults or older children: Good prognosis 95% full recovery Older age: Poor prognosis

49. Councelling Patients should be councelled about perinatal n intimate contact risk of transmission HBV not spread by breastfeeding, hugging, sharing water or utensils Children should not be excluded from school, play ,child care or work Families should not feel obligated to disclose the diagnosis

50. Hepatitis C RNA, Flaviviridae 6 major phenotypes (1-6) Most common cause of CLD in adults HCV is uncommon in the pediatric population Seroprevalence is 0.2 % in < 11 yrs and 0.4 % in ≥ 11 yrs Mode of transmission – Parenteral ( Blood transfusion, Illegal drug abuse) – most common route Sexual transmission – 2 nd most common route Others: occupational exposure 10% have no known risk factor Vertical transmission in children – main – 5 % (in case of HIV coinfection n high DNA titre – 20%) Incubation period= 7-9 weeks.

51. CLINICAL FEATURES: Acute HCV: Mild , insidious onset Nausea Vomitting Pain abdomen Icterus Dark urine Chronic HCV : Most likely to progress to chronic infection

52. Extrahepatic Menifestations Essential mixed cryoglobinemia Cutaneous vasculitis Porphyria cutanea tarda Lichen planus Peripheral neuropathy Cerebritis Polyarthritis Membranoproliferative glomerulonephritis Nephrotic syndrome ASMA, ANA n low thyroid hormones may also be present

53. DIAGNOSIS Detection of antibodies to HCV antigen by EIA ( enzyme immune assay) – canbe negative upto 1-3 months after clinical illness Anti HCV is not a protective antibody and therefore does not confer immunity Detection of Viral RNA by PCR. Usually detectable within 1-2 weeks of exposure .

54. DIAGNOSIS

55. PCR Qualitative PCR Whether the hepatitis C virus is present in the bloodstream or not . More sensitive n accurate – able to detect very low levels of the virus. Useful in patients with recent or perinatal infection, hypogammaglobinmeia , or immunosuppression A negative test 10-12 weeks after finishing hepatitis C treatment – cure Quantitative PCR: Amount of virus present in the bloodstream . Identifying patients who are likely respond to therapy Monitoring response to therapy

56. DIAGNOSIS Genotype: Genotype 1 responds poorly to therapy Genotype 2 n 3 has favourable response to therapy Aminotransferase fluctuate during HCVinfection Liver biopsy – assess presence and extent of hepatic fibrosis US or MRE (magnetic resonance elastography )- estimate degree of fibrosis

57. SCREENING INDICATIONS: Persons who have IV drugs abuse in the recent and remote past. With HIV infection With hemophilia who received clotting factor prior . Who have ever been on hemodialysis . With unexplained abnormal aminotransferase levels. Immigrants from countries with a high prevalence of HCV infection . Children born to HCV-infected mothers Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood Current sexual partners of HCV-infected persons

58. Treatment of Acute HCV Children has a higher spontaneous clearance rate than adults ( 45% till 19yrs ). Those with normal biochemical profile, mild histological change, shorter duration of illness n fewer comorbid conditions – no specific treatment Screen yearly with liver ultrasound and alpha fetoprotein for HCC as well as any clinical evidence of liver disease Vaccination against HAV n HBV to prevent superinfection n ALF In adults – 24-week course (beginning within 2–3 months after onset) of long- acting pegylated interferon plus the nucleoside analogue ribavirin) to prevent chronic liver disease

59. Treatment of chronic HCV Peginterferon plus ribavirin has been approved by FDA for those > 3 yrs SVR: 49% for genotype 1 SVR: 80-90% for genotype 2-3 Treatment considered for those with evidence of advanced fibrosis or injury on liver biopsy

60. TREATMENT KINETICS Null responders: HCV RNA reduction < 2log10 IU/mL Partial Responders: HCV RNA reduction > 2log10 IU/mL but not suppressed to undetectable by week 24. Sustained Virologic Response ( SVR): Undetectable HVC RNA, 24 weeks after therapy completion Rapid virologic response (RVR): HCV RNA undetectable within 4 weeks . Early virologic response (EVR): HCV RNA reduction > 2log10 IU/mL with: HCV RNA undetectable at 12 weeks – complete EVR HCV RNA undetectable at 48 weeks – End treatment response (ETR)

61. GOALS OF THERAPY Attain Sustained Virologic Response Eradicate HCV infection in acute . Decrease HCV associated morbidity and mortality. Normalize biochemical markers . Improve clinical symptoms. Prevent progression to cirrhosis an HCC. Prevent development of end stage liver disease . To prevents the development of chronic HCV infection .

62. TREATMENT OF CHRONIC HCV INFECTION Difficult patient population: Advanced liver disease (fibrosis or decompensated cirrhosis ) Recurrence after liver transplantation . Patients younger than 18 years . Co-infection with HIV or HBV . Chronic Kidney Disease. Non responders or relapses.

63. Monitoring FOLLOW UP: Genotype-1: at 12 weeks Retest HCV RNA level – If Negative or decreased by 2log 10 unit Continue for full 48 wk. Monitor for :Symptoms, Blood count, ALT at 4-8 week interval If RNA hasn’t fallen by 2log 10 Units: STOP therapy Genotype 2, 3: at 24 weeks Retest HCV RNA level. After therapy: Assess ALT 2, & 6 months. Repeat HCV RNA, 6 months after stopping treatment.

64. Hemolytic anemia : Decrease dose to 600 mg/day when Hb drops to 10 g/ dL or less, and discontinue when Hb drops to 8.5 g/ dL or less . May worsen underlying cardiac disease . Monitor complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks . May use erythropoetin or darbepoetin to stimulate red blood cell production, improve anemia. RIBAVIRIN ADVERSE EFFECT MONITORING

65. INTERFERON ADVERSE EFFECTS MONITORING Influenza-like symptoms (e.g., fever, headache, myalgia, fatigue) Hematologic abnormalities: neutropenia, thrombocytopenia, Neuropsychiatric disorders (e.g., depression 40 % and anxiety), injection site reactions, diarrhea, nausea, insomnia, alopecia, pruritis , and anorexia . Management: Hematological: • Anemia : - Tx : Erythropoitic growth factor IFN induced neutropenia: • Recombinant granulocyte colony stimulating factor Thrombocytopenia : thrombopoietin receptor agonist Neuropsychiatric: • Prompt recognition and early treatment required Depression : Close monitoring and follow up by psychiatrist Uncontrolled psychiatric symptoms: contraindication for treatment.

66. Contraindications to treatment Major uncontrolled depressive disorder . Solid-organ transplantation (renal, heart, lung) Autoimmune hepatitis or other autoimmune conditions Untreated thyroid disease . Pregnant or unwilling to adhere to adequate contraception. Severe concurrent medical disease (hypertension, heart failure, coronary heart disease, poorly controlled diabetes mellitus, chronic obstructive pulmonary disease ) Age younger than 2 years . Hypersensitivity to IFN or ribavirin.

67. PREVENTION No Vaccine is available Risk factor modification Sexual contact: appropriate barrier contraception Avoid blood exposure: Occupational (universal precautions) or other contact Screening of blood or blood plasma for anti-HCV Avoid body piercing, sharing razors or receiving a tattoo . HAV and HBV vaccine to prevent further progression of liver disease

68. Hepatitis D RNA virus Defective – only can cause infection along with HBV as it is incapable of making its own coat proteins (outer coat is composed of excess HbsAg ) U ncommon in children but should be suspected in any child with ALF. Co-infection: HDV causing infection at the same time as the initial HBV infection Superinfection: HDV infect a person who is already infected with HBV Incubation Period: (for superinfection) 2-8 weeks , (for coinfection) 45-160days CLINICAL MANIFESTATIONS – Symptoms similar to infection with other hepatitis viruses, but more severe. In co infection, acute hepatitis is more common n much more severe than for HBV alone while risk of chronic infection is low In super infection, acute illness is rare, but chronic hepatitis is common. Risk of acute liver failure is highest

69. Treatment HDV – not yet isolated IgM antibody to HDV – 2-4 weeks after co infection, 10 weeks after super infection Diagnosis: No specific HDV targeted treatments yet, only supportive treatment Control and treat HBV infection without which HDV cannot induce hepatitis. Ongoing trials – Interferons No vaccine available for both Once chronic infection is identified, close follow up and referral to paediatric gastroenterologist is recommended.

70. Hepatitis E RNA virus Epidemic form of what was formerly called as non A non B hepatitis Transmission – fecal-oral route Mean incubation period: 40 days (15-60 days ) Peak age: 15-34 years Pathogenesis: act as a cytopathic virus CLINICAL FEATURES: Similar to that of HAV but more severe. Chronic illness does not occur except in immunocompromised Major pathogen in pregnant women – acute liver failure with higher fatality incidence Can cause decompensation of preexisting chronic liver disease

71. DIAGNOSIS: Detection of IgM antibody 1 week after illness indicate acute infection Detection of Igg antibody indicating chronic infection HEV-RNA can be detected in stool from 1 week prior to the onset of symptoms and for more than 2 weeks after the onset. Treatment: No specific HEV targeted treatments yet liverguardpluse

72. Post test Questions No parenteral transmission occur in the following hepatotropic viruses HAV HBV HCV HDV HEV (correct ans E) HBV is present in high concentrations in serous exudates saliva vaginal fluid semen Urine ( correct ANS A)

73. Post test Questions Risk factors for HBV infection in children and adolescents include acquisition by the following EXCEPT intravenous drug contaminated needles sexual contact intimate contact with carriers sharing toys (correct ANS E Routine screening for HBV infection requires assay of multiple serologic markers, all the following are true EXCEPT HBsAg is the first serologic marker of infection to appear Anti- HBc is a valuable serologic marker of acute HBV infection anti-HBs and anti- HBc are detected in persons immunized with hepatitis B vaccine HBeAg is a marker of infectivity HBsAg levels fall before symptoms wane ( correct ANS C)

74. Post test Questions The disease exists in short-term (acute) and long-term (chronic) forms. How long does acute hepatitis last? Less than 6 months Less than 3 months About 6 weeks 1 month ( correct ANS A) Regarding epidemiology of HBV, the following are true EXCEPT intrauterine infection occurs in 2.5% B . antigenemia appear 1-3 mo after birth C . HBsAg is inconsistently recovered in human milk of infected mothers D . breastfeeding of nonimmunized infants by infected mothers confer a greater risk of hepatitis E . HBV has 8 genotypes (A-H) ( correct ANS D)