Chapter 50 Hepatitis Viruses.pptx education

education

1. Hepatitis Viruses

2. Learning objectives Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

3. Hepatitis viruses H eterogeneous group of viruses that are hepatotropic Cause acute inflammation of the liver producing identical histopathologic lesions Similar clinical illness such as fever, nausea, vomiting, and jaundice. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

4. Properties HAV HBV HCV HDV HEV Common name Infectious hepatitis Serum hepatitis Non A non B or post-transfusion hepatitis Delta agent Non A non B enteric transmitted hepatitis Family Enterovirus-72 (Picornaviridae) Hepadnaviridae Flaviviridae Unclassified viroid-like Unclassified Caliciviridae-like Genus Hepatovirus  Orthohepadnavirus  Hepacivirus  Deltavirus  Hepevirus   Virion 27 nm, icosahedral 42 nm, spherical 60 nm, spherical 35 nm, spherical 30–32 nm, icosahedral Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Classification

5. Classification (cont..) Properties HAV HBV HCV HDV HEV Envelope No Yes (HBsAg) Yes Yes (HBsAg) No Genome ssRNA dsDNA ssRNA ssRNA ssRNA Stability Heat and acid-stable Acid-sensitive Ether-sensitive, acid-sensitive Acid-sensitive Heat-stable Onset Abrupt Insidious Insidious Insidious Abrupt Age Children, Young adults Young adults babies, toddlers Any age, but more common in adults Any age (similar to HBV) Young adults (20–40 years) Route Feco -oral Blood (MC) Sexual, Vertical Blood (MC) Sexual(+/-) Vertical(+/-) Blood (MC) Sexual(++) Vertical(+) Feco -oral Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

6. Classification (cont..) Properties HAV HBV HCV HDV HEV I.P (days) 15–45, (Average 30) 30–180, (Average 60–90) 15–160, (Average 50) 30–180, (Average60–90) 14–60, (Average 40) Fulminant disease Rare (0.1%) Rare (0.1–1%) Rare (0.1%) Frequent (5–20%) Usually rare(1-2% ) Pregnancy- 20-40% Carrier None Yes (0.1–30%) Yes (1.5–3.2%) Variable None Chronicity None Occasional (1–10%) Common (85%) Common None Oncogenic No Yes (neonate) Yes +/- No Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

7. Properties HAV HBV HCV HDV HEV Prevalence High High Moderate Low, regional Regional Associated other feature Secondary attack rate 10-20% HCC, cirrhosis, Autoimmune disorder like AGN, arthritis, PAN HCC, cirrhosis, Autoimmune- AGN, arthritis, cryoglobulinemia HCC, cirrhosis, fulminant hepatitis Secondary attack rate (1-2%) Rarely seen in western countries Prognosis Excellent Worse with age Moderate Acute-good Chronic- poor Good Prophylaxis Immunoglobulin, Inactivated vaccine HBIG, Recombinant vaccine None HBV vaccine (no vaccine for HBV carriers) Vaccine (HEV239) (only in China) Therapy None Pegylatedinterferon Lamivudine Pegylated interferon plus ribavirin Interferon ± None Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Classification (cont..)

8. HEPATITIS A VIRUS O riginally designated as ‘ enterovirus 72’. Morphology 27 to 32nm Spherical particle with icosahedral symmetry Linear ssRNA O nly one serotype, does not cross-react with other hepatitis viruses Typed into seven genotypes based on gene sequences. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

9. Resistance Relatively resistant to disinfectants. S table to acid, heat (60°C for 1 hour), and ether (20 %) Preserved in dried state for 1 month and stored for years at -20°C. D estroyed by autoclaving, by boiling in water for 5 minutes, by hot air oven, by UV rays and by treatment with formalin or chlorine (10–15 ppm for 30 minutes). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

10. Mode of transmission Feco -oral route Infection is by ingestion. Rarely, sexual (homosexuals through oro -genital contact) and parenteral routes (infected blood products or needle pricks) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

11. Epidemiology Hosts- Humans Age: Children and adolescents (5- 14 years of age) are most commonly affected M ajority remain subclinical (80–95%),but excrete virus in feces for longer time. Adults are more icteric (75–90%) than with higher mortality rate Anicteric to icteric cases ratio is about- In children – 12:1 In adults – 1:3 Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

12. Outbreaks are common in summer camps, day care centers , families and institutions, neonatal ICUs, and among military troops. Recurrent epidemics and sudden, explosive epidemics are common and usually result from fecal contamination of a single source ( e.g , drinking water, milk or food such as raw vegetables, salad,frozen strawberries, green onions and shell fish). The largest epidemic was reported from Shanghai (1988, >3 lakh cases) Seasonal incidence – Though HAV infection is widespread throughout the year, it tends to peak in late rainfall and in early winter. Virus excretion -Viral excretion in feces may be 2 weeks before to 2 weeks after the appearance of jaundice (however, viremia occurs from -2 weeks to +1 week of jaundice). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

13. Risk factors Poor personal hygiene and overcrowding Adults have protective antibodies and are mostly immune. However, in developed countries with improved hygiene, the incidence is decreasing and there is trend of shift of infection towards the older age . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

14. Clinical manifestations Incubation period - 15–45 days (mean 30 days). Onset is relatively abrupt (sub-acute). Pre-icteric phase (predominant GI symptoms such as nausea and vomiting) followed by Icteric phase or jaundice (dark urine , yellowish sclera and mucus membrane) Complete recovery occurs in most (98%) cases. N o chronic or carriers state Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

15. Complications Fulminant hepatitis Relapsing hepatitis Cholestatic hepatitis Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

16. Laboratory Diagnosis Anti HAV Antibody detection IgM antibodies appear during the acute phase, peak about 2 weeks after the elevation of liver enzymes, and disappear within 3–6 months IgG appears a week after the appearance of IgM and persists for decades. Interpretation- Anti-HAV IgM positive- Indicates acute infection Anti-HAV IgG antibody detection in the absence of IgM indicates past infection or recovery. ELISA is the method of choice Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

17. Course of HAV markers with symptoms Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

18. Detection of HAV particles by immune electron microscopy HAV appears in stool from -2 to +2weeks of jaundice . Also detected from liver, bile, & blood. Detection of HAV antigens in stool by ELISA-from -2 to +2weeks of jaundice Isolation - HAV is the only hepatitis virus where isolation has been attempted. Non-specific- elevated liver enzymes and serum bilirubin level Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Laboratory Diagnosis

19. Treatment N o specific antiviral drug available Prevention and containment of infection Hand washing before and after use of toilet Sanitary disposal of infected fecal material- by disinfection with 0.5% hypochlorite Purification of drinking water by effective filtration and adequate chlorination (with at least 1mg/L of residual chlorine). Use of boiled water (boiling for at least 5 min) during outbreaks. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

20. Vaccines Formaldehyde Inactivated vaccine: Prepared from human fetal lung fibroblast cell lines - MRC-5 and WI 38 Given to children after 12 months of age Single dose is administered by IM route (deltoid) followed by booster at 6-12months gap. Protective efficacy - 94 %. Live attenuated vaccine is given as single dose, subcutaneously. Uses H2 and L-A-1 strains, prepared in human diploid cell line (China). Both vaccines are highly immunogenic, produce long lasting immunity, possibly life-long. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

21. Human Immunoglobulin(HAV-Ig) F or post-exposure prophylaxis of intimate contacts (household, day care centres ) Dose - 0.02 mL/kg ( protection – 1 to 2months). A dministered as early as possible after exposure; (within 2 weeks). N ot necessary for: Already vaccinated Casual contacts (office, factory, school, or hospital) Elderly persons (likely to be immune). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

22. HEPATITIS B Discovered by Blumberg in 1963 . Morphology: Electron microscopy of serum of the patients infected with HBV reveals three morphologic forms: Spherical forms ( made up of HBsAg) -most numerous, small forms measuring 22 nm in diameter. Tubular or filamentous forms (made up of HBsAg) - also have the same diameter but 200 nm long. Complete form or Dane particles (less frequent). They are larger, 42-nm size spherical virions ; made up of- Outer surface envelope - HBsAg (Hepatitis B surface antigen) Inner 27 nm size nucleocapsid - consists of core antigen ( HBcAg ) and pre-core antigen( HBeAg ) and partially double stranded DNA Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

23. Viral antigens Hepatitis B surface antigen (HBsAg ) P reviously called as 'Australia antigen‘ A ntigenically complex and contains two components: Common group reactive antigen ‘a’ epitope Two pairs of type specific antigens d/y and w/r;­ only one member of each pair being present at a time. F our subtypes of HBsAg - adw , ayw , adr , and ayr . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

24. Viral antigens Hepatitis B core antigen ( HBcAg ) F orms the intracellular core protein N ot secreted Does not circulate in blood Can be demonstrated in hepatocytes by immunofluorescence . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

25. Viral antigens Hepatitis B pre core antigen ( HBeAg ) N on-particulate soluble antigen possessing a signal protein which enables it to be secreted. Present in circulation. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

26. Typing of HBV - Serotypes HBV is divided into four major serotypes ( adr , adw , ayr , ayw ) - Based on antigenic epitopes present on its envelope protein HBsAg. Serotypes - not important in immunity as the dominant ‘a’ antigen is shared by all, but they are useful for epidemiologic investigations, as all the cases during an epidemic would likely to have the same subtype. Serotypes exhibit distinct geographical distribution: adw - predominant sub type in Europe, Australia and America. a dr - South and East India ayw - Western and Northern India Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

27. Typing of HBV- Genotypes HBV can also be divided into eight genotypes ( A–H) According to overall nucleotide sequence variation of the genome. Genotypes A and D are prevalent in India. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

28. Viral genome P artially circular dsDNA, of 3200 bp in length. minus strand of DNA (L or long strand)is complete and full-length and is identical in all HBV isolates The positive strand (S or short strand) is incomplete and of variable length (50-80%). HBV genome is compact and consists of four overlapping genes : S gene C gene X gene P gene Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

29. Viral genome- S gene T hree regions- S, pre-S1 and pre-S2 Code for surface antigen (HBsAg ) S region codes for the major protein (S). Product of S region plus the adjacent Pre-S2region is the middle (M) protein Pre-S1, Pre-S2combines with S to code for Large (L) protein. The L protein is present only in the virion , while the M and S proteins are found in the circulating HBsAg particles also. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

30. Viral genome- C gene C onsists of pre-C and C-regions, which code for two nucleocapsid proteins Pre-C region codes for HBeAg C-region codes for HBcAg Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

31. Viral genome- X gene Codes for HBxAg , which can activate the transcription of cellular and viral genes. C ontribute to carcinogenesis by binding to p53. HBxAg and its antibody are elevated in patients with severe chronic hepatitis and hepatocellular carcinoma. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

32. Viral genome- P gene L argest and codes for polymerase (P) protein which has three enzymatic activities DNA polymerase activity Reverse transcriptase activity RNase H activity Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

33. Hepatitis B virus mutants Pre-core mutants: have defect in pre-core region of C gene which leads to their inability to synthesize HBeAg . Mutation - Nonsense mutation in the pre-C gene leading to formation of premature stop codon. Geographical distribution - Mediterranean countries and in Europe. Patients infected with precore mutants may be diagnosed late and they tend to have severe chronic hepatitis that progresses more rapidly to cirrhosis. Markers -They lack HBeAg . Other viral markers are present as such . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

34. Hepatitis B virus mutants Escape mutants: Mutations in the S gene leads to alteration of HBsAg. Mutation occurs in the immunodominant a antigen of HBsAg Escape mutants are observed in three situations- Infants born to HBeAg positive mothers Liver transplant recipients who underwent the procedure for hepatitis B and who were treated with a high-potency human monoclonal anti-HBs preparation. A small proportion of recipients of active and passive immunization, in whom antibody pressure may favor evolutionary change in gene coding a antigen Pose problems in hepatitis B vaccination strategies as well as in the diagnosis of the disease . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

35. Hepatitis B virus mutants YMDD mutation : HBV infected patients on lamivudine therapy May develop resistance to the drug due to mutation in the YMDD locus of the HBV reverse transcriptase region of polymerase gene. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

36. Hepatitis B replication Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

37. Transmission Parenteral route - Via blood & blood products transfusion and needle prick injuries or by inoculation during surgical or dental procedures or percutaneous inoculation via shared razors and tooth brushes. HBV ( 30% ) is more infectious than HIV ( 0.3% ) and HCV ( 3% ). As little as 0.00001 ml of blood can be infectious. Sexual transmission Vertical (perinatal) transmission- Risk is maximum if the mother is HBeAg positive Transmission occurs at any stage ; in utero, during delivery ( maximum risk) and during breast feeding Direct skin contact Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

38. Transmission High risk groups which are more prone for acquiring infection are: Surgeons(maximum risk) Paramedical workers Sex workers especially homosexual males Recipients of blood transfusion and organ transplantation Drug addicts Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

39. Epidemiology Reservoir of infection- Humans are the only reservoir Cases may range from inapparent to symptomatic cases. Carries may be temporary (harbour the virus for weeks to months) or persistent/ chronic (harbour the virus for > 6months). Carriers can also be grouped into- Simple carriers- Low infectivity, transmit the virus at a lower rate. They possess low level of HBsAg and no HBeAg . Super carriers- Highly infectious and transmit the virus efficiently. They possess higher levels of HBsAg and also have HBeAg , DNA polymerase, and HBV DNA . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

40. Epidemiology Prevalence- Based on HBsAg carrier rates, Type 1 pattern (low endemicity)- Carrier rate is <2%. It is observed in SriLanka and Nepal. Type 2 pattern (intermediate endemicity) – Carrier rate is between 2-8%. It is observed in India, Bhutan, Indonesia and Maldives. Type 3 pattern (high endemicity)-Carrier rate is >8%. It is observed in Bangladesh and DPR Korea. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

41. Situation in the world World Hepatitis Day is celebrated on 28th July every year. WHO estimates that in 2015 , about 257 million population were living with chronic HBV infection with a global prevalence of 3.5%. 2.7 million persons were co-infected with HBV and HIV The widespread use of HBV vaccine in infants has led to a considerable reduction in the incidence of new chronic HBV infections. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

42. Situation in India I ntermediate level of HBV endemicity (3.7% prevalence ). 40 million HBV carriers, which constitutes 11 % of the estimated global burden, which is second highest to China (30%) Highest prevalence recorded from Andamans and Arunachal Pradesh Tribal areas, the prevalence is extremely high (19 %) than non-tribal populations HBV accounts for 40–50% of hepatocellular carcinoma (HCC) and 10–20% of cirrhosis in India. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

43. Epidemiology (cont..) HBV followed by HCV are the most common cause of: Chronic hepatitis Cirrhosis : HBV accounts for 30% of cirrhosis Hepatocellular carcinoma (HCC): HBV accounts for 45 % of HCC Post-transfusion hepatitis : HBV (1:220,000)> HCV (1:1800,000 ). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

44. Epidemiology (cont..) Resistance- HBV can be destroyed by hypochlorite and heat (autoclave). Period of infectivity: People infected with HBV are said to be infectious as long as the HBsAg is present in blood i.e. during incubation period (a month before jaundice) up to several months thereafter (occasionally years for chronic carriers). Become non-infectious once HBsAg disappears and is replaced by anti-HBs antibody. Maximum infectivity is observed when HBeAg is elevated in serum. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

45. Epidemiology (cont..) The global HBV prevalence in HIV-infected persons is 7.4 %. Conversely, about 1% of HBV-infected persons are also infected with HIV. The highest burden (71 %) for HIV–HBV coinfection is found in sub-Saharan Africa Although HBV does not alter the progression of HIV , the presence of HIV greatly enhances the risk of developing HBV-associated cirrhosis and liver cancer Tenofovir , a drug recently included in the treatment regimen of HIV is also active against HBV. This may have a role in controlling HIV-HBV coinfection. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

46. Various outcomes of HBV infection Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

47. Epidemiology (cont..) Age- The outcome of HBV infection depends on the age. Following HBV infection- Chance of developing acute hepatitis is directly related to the age- 1% (perinatal) 10% (early childhood; 1-5 years age) 30% (late child hood; after 5 years age) Chance of developing chronic hepatitis or carrier state is inversely related to age- 80-90% (perinatal) 30% (early child hood; 1-5 years age) 5% (late child hood; after 5 years age) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

48. Epidemiology (cont..) Age- The outcome of HBV infection depends on the age. Explanation- Pathogenesis HBV infection is immune mediated Hepatocytes carrying viral antigen are subjected to NK cell mediated antibody dependent cell cytotoxicity(ADCC) or CD8 T cell mediated cytotoxicity Absence of an effective immune system (infants) - leads to carrier state Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

49. Clinical Manifestations Incubation period - 30–180 days. Onset is slow and insidious Patients may present with subclinical infection or acute or chronic hepatitis Clinically, HBV infection is indistinguishable from other hepatitis viruses; characterized by- Pre-icteric phase (predominant gastrointestinal symptoms such as nausea and vomiting) followed by Icteric phase or jaundice Clinical outcome may be either development of carrier state or complete recovery. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

50. Complications Hepatic complications: Fulminant hepatitis Cirrhosis Hepatocellular carcinoma. Extrahepatic complications: Prodromal phase - Serum sickness-like syndrome (5–10 % of patients) This is due to immune complex deposition. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

51. Laboratory diagnosis Viral markers of HBV infection: Definitive diagnosis of hepatitis B depends on the serological demonstration of the viral markers which can be classified as- Antigen markers- HBsAg and HBeAg Antibody markers- Anti-HBs, Anti- HBe and Anti- HBc Molecular markers- HBV DNA Non-specific markers- elevated liver enzymes and serum bilirubin Detection method – ELISA, ICT Viral DNA can be detected by PCR; but quantified by real time PCR . HBV does not grow in any conventional culture system. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

52. Serological markers of hepatitis B virus in various stages of hepatitis B virus infection Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

53. Hepatitis B surface antigen (HBsAg ) F irst marker to be elevated following infection; appears within 1–12 week (usually between 8–12 weeks of infection) A ppears during incubation period;2–6 weeks before the biochemical and clinical evidence of hepatitis. Presence of HBsAg indicates onset of infectivity (i.e. patient is capable of transmission of HBV) R emains elevated in the entire duration of acute hepatitis; Becomes undetectable 1-2 months after the onset of jaundice or Rarely persists beyond 6 months during chronic hepatitis and carrier state HBsAg is used as an epidemiological marker of hepatitis B infection. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

54. Hepatitis B precoreantigen ( HBeAg ) and HBV DNA Appear concurrently with or shortly after appearance of HBsAg in serum They are the markers of Active viral replication High viral infectivity (i.e. they are highly infectious to others) Present in either acute, chronic and carrier state and it cannot differentiate between these stages. Indicates that the virus is actively multiplying, which could be either- Acute active hepatitis Chronic active hepatitis Or a carrier in whom HBV is actively multiplying and highly infectious Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

55. Hepatitis B coreantigen ( HBcAg ) Hidden antigen due to surrounding HBsAg coat . Also non-secretory in nature - hence, it cannot be detected in blood. HBcAg may be detected in hepatocytes by immunofluorescence microscopy . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

56. Anti- HBc Anti- HBc IgM(Hepatitis B core antibody) Anti- HBc IgM is the first antibody to elevate following infection. Appears within the first 1–2 weeks after the appearance of HBsAg and lasts for 3-6months. Indicates acute hepatitis B infection, O nly marker (sometimes anti- HBc IgG)present during the period between appearance of anti-HBs antibody and disappearance of HBsAg. Anti- HBc IgG (Hepatitis B core antibody) Appears in late acute stage and remains positive indefinitely whether the patient proceeds to Chronic stage (with persistence of HBsAg, symptomatic and elevated liver enzymes) Carrier state (with persistence of HBsAg but asymptomatic) or Recovery (appearance of Anti-HBs antibody) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

57. Anti- HBe (Hepatitis B pre-core antibody) A ppear after the clearance of HBeAg and remain elevated for variable period S ignifies diminished viral replication and decreased infectivity. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

58. Anti-HBs (Hepatitis B surface antibody ) Appears after the clearance of HBsAg and remains elevated indefinitely Indicates recovery , immunity and non-infectivity (i.e. stoppage of transmission) O nly marker of vaccination. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

59. Interpretation of markers in various stages of hepatitis B infection Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe Symptoms Liver enzymes DNA Interpretation + - - - - Absent Normal + Early acute hepatitis (Incubating) + – IgM + – Present Elevated + Acute hepatitis B, high infectivity + – IgG ++ – Present Elevated ++ Chronic hepatitis B, high infectivity (Immunoreactive chronic hepatitis) + – IgG – + Present Elevated + Chronic hepatitis B, low infectivity (Chronic inactive hepatitis) + - IgG + - Absent Normal ++ Immuno tolerant chronic HBV infection (previously called as super carriers)

60. Interpretation of markers in various stages of hepatitis B infection Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe Symptoms Liver enzymes DNA Interpretation + - IgG - +/- Absent Normal + Chronic inactive HBV infection (previously called as simple carriers) + – IgG – - Present Elevated + Precore–mutant hepatitis B infection - - IgG -/+ -/+ Present Elevated + Escape mutant hepatitis B infection - + IgG - +/– Absent Normal - Recovery - + - - - Absent Normal - Post vaccination - - IgG - - Absent Normal + Occult hepatitis B infection

61. Treatment of Hepatitis B Most acute hepatitis B infection is self-limiting; do not require any specific treatment . In contrast, treatment of chronic hepatitis B has perceived many recent advances. With the advent of newer antiviral drugs, now it’s possible to contain the disease . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Adapted from EACL guideline 2017 (European Association for the Study of the Liver)

62. Treatment of Hepatitis B Indications The indications to initiate treatment for patients with hepatitis B infection are: Acute hepatitis with acute liver failure (coagulopathy or encephalopathy) Chronic active hepatitis ( immunoreactive hepatitis, HBeAg+ve ) Chronic inactive hepatitis ( HBeAg-ve ) HBV DNA > 2,000 IU/ml plus ALT ↑ (> normal) plus moderate degree of liver fibrosis HBV DNA > 20,000 IU/ml and ALT ↑↑(>2 times normal); regardless of the degree of liver fibrosis Associated cirrhosis (regardless of ALT level, viral load) Super carriers or immunotolerant hepatitis (if >30 years age) Carriers (super or simple) with family history of HCC or cirrhosis Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Adapted from EACL guideline 2017 (European Association for the Study of the Liver)

63. Antiviral agents Antiviral agents (nucleoside analogues)- such as telbivudine and tenofovir . Lamivudine , adefovir , entecavir were used previously; now not in use because of high risk of developing resistance. Pegylated interferon alfa (used previously; now not in use because of adverse effects)  Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

64. Treatment options available for chronic hepatitis B infection   Interferon alfa Antiviral agents ( Telbivudine and tenofovir ) Route and dosage Subcutaneous, weekly Oral, daily Mode Monotherapy Monotherapy Duration 48 weeks Long-term until HBsAg loss Side effects High Minimal Decompensated disease, immuno- compromised patients Cannot be given Can be given HBV DNA <2000 IU/mL Undetectable i.e. <10 IU/mL HBsAg loss or HBeAg seroconversion Occurs relatively earlier (1 year) Occurs very slowly Preference Was preferred in past. First choice of treatment currently. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers **HBV DNA clearance from blood may occur early; however cccDNA may be present in hepatocytes quiescently; which may get activated later. Hence, HBeAg seroconversion (for previously HBeAg positive cases) and loss of HBsAg with seroconversion are more reliable indicator of successful therapy.  

65. Prophylaxis Active Immunization (Hepatitis B Vaccine) Hepatitis B vaccine is a recombinant subunit vaccine. The surface antigen (HBsAg) is used as vaccine candidate which is prepared in Baker’s yeast by DNA recombinant technology by cloning the S gene into the yeast chromosome Route of administration: Intramuscular route over deltoid region (in infant- anterolateral thigh) Dosage : 10–20 µg/dose (half of the dose is given to children below 10 years ) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

66. Prophylaxis Active Immunization (Hepatitis B Vaccine) Schedule : Recommended schedule for adults: Three doses are given at 0, 1 and 6 months Under national immunization schedule: It is given at 6 , 10, 14 weeks (along with DPT vaccine). Additional dose at birth may be given in areas with prevalence of HBV more than 8 %. Minimum interval between the doses—4 weeks If there is documentation of partial vaccination (1 or 2 doses ): Then do not restart; just complete the vaccine series regardless of when the last dose was taken. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

67. Prophylaxis Active Immunization (Hepatitis B Vaccine) Marker of protection: Recipients are said to be protected if they develop seroconversion with an anti-HBsAg antibody titer of more than 10 mIU /mL Re-vaccination: If titer remain <10 mIU /mL after first series of vaccination; the HCW is subjected to second series of vaccination (3 doses at 0, 1, 6 months) Non/low responders: About 5–10% of individuals mount an impaired immune response following vaccination. They may be either: Non-responders (do not show seroconversion after two series of vaccination; i.e six doses of vaccination.) or; Low responders (seroconversion occurs slowly after the second series of vaccination.). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

68. Prophylaxis Active Immunization (Hepatitis B Vaccine) Seroconversion: 95 % of infants, children and young adults Older people (>60 years), the protection is about 65–75% only Protection may last for about 30 years or even longer Booster doses are not needed: The health care workers once protected, should not check their titer again or should not take booster vaccines. They remain protective even if the titer falls <10 mIU / mL. This is because the memory cells get stimulated much faster and the titer rises very soon following an infection with HBV Newer vaccine containing whole HBsAg (i.e. product of Pre S1 + Pre S2 + S genes) is under development which may provide a better seroconversion. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

69. Passive immunization (Hepatitis B Immunoglobulin or HBIG) Indications: HBIG is used in the following situations where an immediate protection is warranted. Acutely exposed to HBsAg positive blood- e.g. surgeons, nurses, laboratory workers Sexual contact of acute hepatitis B patients Neonates borne to hepatitis B carrier mothers Post liver transplant patients who need protection against HBV infection Following accidental exposure, HBIG should be started immediately (ideally within 6hr, but not later than 48 hrs ). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

70. Passive immunization (Hepatitis B Immunoglobulin or HBIG) Recommended dose - 0.05-0.07ml/kg body weight , two doses of HBIG should be given 30 days apart HBIG gives short term passive protection which lasts for about 100 days. Since the median incubation period is less than 100 days, two doses given one month apart should suffice. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

71. Combined immunization Combined immunization with HBIG + vaccine is more efficacious than HBIG alone . Recommended for neonates born to HBV infected mother, where a single injection of 0.5 ml of HBIG is given to the neonate immediately after the birth, followed by full course of vaccine given at a different site (the first dose being given within 12 hours of birth). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

72. General Prophylactic Measures Screening of blood bags, semen and organ donors Following safe sex practices (e.g. using condoms, avoiding multiple sex partners) Following safe injection practices - use of the disposable syringes and needles Following safe aseptic surgical practices Health education Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

73. HEPATITIS C VIRUS – Morphology Family flaviviridae , genus Hepacivirus . S pherical , 60 nm size Enveloped virus Nucleic acid- It contains positive sense ssRNA Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

74. HEPATITIS C VIRUS – Morphology Proteins- HCV possesses Four structural proteins, the nucleocapsid core protein C; two envelope glycoproteins (E1 and E2) and a membrane protein p7 (functions as an ion channel) Six non-structural (NS) proteins-NS2, NS3, NS4A, NS4B, NS5A, and NS5B Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

75. Genetic diversity of HCV Similar to HIV, Hepatitis C virus displays diversity in the RNA genome that occurs because of high rates of mutations seen in the virus which in-turn is due to ( i ) the high replicative activity and (ii) the lack of proofreading activity of the RNA polymerase. Genotypes : HCV is divided into six major genotypes or clades , which differ from each other by 31–33% in their RNA sequence Subtypes : Genotypes are further divided into more than 100 subtypes, which differ from each other by 20–25 % in their RNA nucleotide sequence. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

76. Genetic diversity of HCV E2 envelope protein is the most variable region of the entire HCV genome followed by the non-structural proteins (especially, NS5B encoded RNA polymerase); M ore prone to undergo mutations Unfortunately , E2 protein happens to be the target against which most of the neutralizing (protective) antibodies are produced D iversity in the gene coding E2 protein enables the emergent mutant virus strains to escape from host’s humoral immunity, which in turn can result in: Establishment of chronic infection Failure of development of effective vaccine. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

77. HCV genotypes vary in their epidemiological distribution : Genotype 1 and 2 - Western countries Genotype 3 - South and East Asia with subtype 3a common among IV drug users from Europe Genotype 4 - North Africa and Middle-East Genotype 5 - South Africa Genotype 6 - Asia In India, genotypes 1 and 3 are more prevalent. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Genetic diversity of HCV

78. Transmission V arious modes of transmission are- Parenteral- HCV is most commonly transmitted through exposure to infectious blood- Recipients of contaminated blood transfusions, blood products or organ transplantations Contaminated needles and sharps pricks Injection drug users Vertical transmission from infected mother to fetus may occur but at much lower rate(6%) than that of HBV(20 %). Sexual transmission (rare) HCV doesn’t spread through breast milk, food or casual contacts including hugging or kissing Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

79. Clinical manifestations Incubation period - 15–160 days (average 50 days ). Following an infection with HCV- About 20% of people develop acute hepatitis; characterized by symptoms similar to that of other hepatitis viruses described earlier. About 75-80% directly develop chronic disease; out of which- 60-70% develop chronic hepatitis 5-20% develop cirrhosis 1-5% develop hepatocellular carcinoma. (HCV accounts for 25% of total liver cancer patients) Extrahepatic manifestations- Due to deposition of circulating immune complexes in various extra hepatic sites , various manifestations can set in such as- Mixed cryoglobulinemia Glomerulonephritis Arthritis and joint pain Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

80. Epidemiology Hepatitis C virus infection occurs worldwide. Every year , 3–4 million people are infected with HCV with more than 3.5 lakhs deaths. Population prevalence rate: About 3% of the world population has been infected with HCV worldwide with more than 170 million chronic carriers Higher prevalence rates have been documented from Africa (up to 10%) followed by South America and Asia In India, the prevalence of HCV is about 1%. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

81. Laboratory Diagnosis- HCV antibody detection assay (ELISA) ELISA is the most common platform used; followed by rapid test and chemiluminescence formats. First and second generation ELISA (used previously) - These assays were using limited HCV antigens (core, NS3 and NS4) for detection of antibodies. These assays are now obsolete as they are less sensitive (not able to detect few genotypes) and used to become positive only after 10 weeks of infection. Third generation ELISA: S tandard method for HCV serology. It employs antigens from NS5 region in addition to core, NS3 and NS4 regions. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

82. Laboratory Diagnosis- HCV antibody detection assay (ELISA) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Advantages Disadvantages Increased sensitivity and specificity (> 99%); These assays detect IgG antibodies to HCV, hence they do not discriminate between active or past infection; for which HCV RNA test is required Not influenced by HCV genotype False positive result- seen in with autoimmune diseases, mononucleosis, and pregnancy Becomes positive in 5 weeks of infection. False negative result- seen in with immunosuppression such as HIV infection, transplant recipients etc.

83. Laboratory Diagnosis- Recombinant immunoblot antibody assay (RIBA) Used in past as a supplementary test to confirm the ELISA result; not in use currently. Works based on the principle of western blot . D etects antibody against core, E2 hypervariable region and NS3, NS4A, NS4B and NS5A regions. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

84. Laboratory Diagnosis- HCV core antigen assay Automated quantitative HCV antigen test detecting core antigen has been available recently (e.g. Abbott ARCHITECT HCV antigen assay). This test is less expensive and less time consuming than HCV RNA PCR. Advantages: Antigen detection assays can be used as an alternative to HCV RNA testing for: ( i ) diagnosis of active/current infection, (ii) monitoring response to treatment. Disadvantage : They are less sensitive than RT-PCR; hence not recommended for blood screening purpose. An ELISA format has recently been available that detects simultaneously antigen (core Ag) and antibody (to NS3 and S4 Ag ). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

85. Laboratory Diagnosis- Molecular methods Real time reverse transcriptase PCR detecting HCV RNA has been the gold standard method for: Confirmation of active HCV infection. Quantification of HCV RNA for monitoring the response to treatment. For determining HCV genotype and subtype (also done by sequence based method). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

86. Diagnosis of acute HCV infection Most cases of HCV infections remain asymptomatic in early stage and are directly presented with chronic infection (i.e. after 6 months). Acute HCV infection (i.e. onset of symptoms within 6 months of exposure) occurs very rarely. Both IgM and IgG antibodies appear during acute stage; IgM may persist during chronic stage for variable time; whereas IgG persists for long duration both in chronic stage and during recovery. Most assays available detect IgG antibodies. There is no IgM based assay available currently. The acute infection can be diagnosed by: ( i ) anti-HCV IgG sero -conversion, (ii) HCV RNA positivity or (iii) IgG avidity assay (low avidity indicates acute infection, strong avidity- may indicate chronic/past infection). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

87. Diagnosis of acute HCV infection Most cases remain asymptomatic in early stage and are directly presented with chronic infection (i.e. after 6 months). Acute HCV infection (i.e. onset of symptoms within 6 months of exposure) occurs very rarely. Both IgM and IgG antibodies appear during acute stage: IgM may persist during chronic stage for variable time IgG persists for long duration both in chronic stage and during recovery. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

88. Algorithm of HCV diagnosis (Adapted from CDC guideline, 2013)   Tes t ou tc ome   Interpr e t a tion   Furthe r a c tions to be taken   H C V a n ti bo dy non- r ea c ti v e   No H C V a n tibody de t e c t ed Repo r t ed as non- r ea c ti v e. No fu r ther a c tion r equi r e d . I f history of r e c e n t e xposu r e within 6 months, then : Do f oll ow -up t esting f or H C V a n tibody (for immunocompetent patient) Test for H C V RNA (for immunocompromised patient)   H C V a n ti bo dy R ea c ti v e   P r esumpti v e H C V in f e c tion A r epe at edly r ea c ti v e r esult indicates either: ( i )cu r r e n t H C V in f e c tion, or (ii) past H C V in f e c tion th a t has r esol v e d , or (iii) biolo g ic false positivi t y f or H C V a n tibod y . H C V RNA PCR should be done - t o ide n tify cu r r e n t in f e c tion.   Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

89. Algorithm of HCV diagnosis (Adapted from CDC guideline, 2013)   Tes t ou tc ome   Interpr e t a tion   Furthe r a c tions to be taken H C V a n ti bo dy r ea c ti ve , H C V RNA de t e c t ed C u r r e n t H C V in f e c tion P r o vide app r op r i at e c ounselling to the patient and refer to HCV clinic. Repeat H C V RNA PCR should be done before initiating tre a tme nt . H C V a n ti bo dy r ea c ti ve , H C V RNA not de t e c t ed No cu r r e n t H C V in f e c tion No fu r ther a c tion r equi r ed in most case s . If clinically suspected or history of exposure within 6 months : then f oll o w up with H C V RNA t esting and app r op r i at e c ounselli ng . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

90. Treatment Hepatitis C The goal of treatment in HCV infection is: To prevent development of complications such as cirrhosis and liver cancer. To achieve sustainable viral response (SVR) which defined as undetectable HCV RNA in blood (≤15 IU/ml) at the end of treatment. Interferon alfa plus ribavirin Earlier, pegylated -interferon (PEG-IFN) alpha plus ribavirin (RBV) was used for treatment of HCV infection. This was associated with intolerable adverse effects with a moderate degree of viral clearance (SVR 40- 50%). Direct-acting antiviral agents (DAAs) After the discovery of direct-acting antiviral agents (DAAs), the treatment of HCV infection has been revolutionized. DAAs are the now the treatment of choice for HCV infection as they can produce SVR rate up to 90% with minimal side effects. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

91. Treatment Hepatitis C Three classes of DAAs are available: NS3/4A (proteases) inhibitors, NS5B (polymerases) inhibitors and NS5A inhibitors. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers Class Agents Directly acting antiviral agents (DAAs) NS3/4A inhibitors (proteases) Ends with suffix ‘previr’ Grazoprevir Paritaprevir , Simeprevir NS5B inhibitors (polymerases) Ends with suffix ‘buvir’ Dasabuvir, Sofosbuvir NS5A inhibitors Ends with suffix ‘asvir’ Daclatasvir, Ledipasvir, Velpatasvir Other classes   Interferons Pegylated interferon alfa-2a & 2b Nucleoside inhibitor Ribavirin

92. Treatment Hepatitis C Combination therapy: The treatment regimen for HCV includes combinations of different DAAs with or without PEG-IFN and ribavirin. Genotype specific: The drugs to be included in the regimen depends upon the genotype detected. Most DAAs are genotype specific; except sofosbuvir / velpatasvir which are active against all genotypes. Duration: Either 12 or 24 weeks; depending up on the HCV genotype and associated liver cirrhosis. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

93. Predictors of Treatment Response Genotypes : HCV genotype 1 and 4 are associated with poor prognosis than other genotypes Stage of disease and associated co-infections such as HIV and HBV: associated with poor prognosis Adherence : Poor compliance to treatment, is associated with worse prognosis Viral RNA load: Higher the viral load (> 800,000 IU/mL ), worse is the prognosis Interleukin 28 B is a strong inducer of interferon-a. People possessing a subtype of IL 28B (called CC genotype ), produce a stronger immune response to HCV infection by inducing IFN-a release; hence have a better outcome Race : Caucasians and African Americans lack CC genotype - poor treatment response than Asians Others : Metabolic disorders such as insulin resistance , obesity metabolic syndrome, steatosis, lack of vitamin D supplement , older age, alcohol consumption—all reduce the chance of responding to HCV therapy. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

94. Prevention No effective vaccine available for HCV . General prophylactic measures are essentially same as that for HBV. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

95. HEPATITIS D Hepatitis D is a defective virus; cannot replicate by itself; depends on Hepatitis B for its survival. Morphology: Hepatitis D is taxonomically unclassified though resembles viroids . It is small in size(35nm), consisting of- Circular, negative-sense ssRNA Protein coat made up of single protein called as- hepatitis D antigen ( HDAg ) Surrounded by envelope protein derived from HBsAg from hepatitis B; hence it is called as defective virus. Transmission: Transmission is similar to that of HBV and HCV. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

96. Association of HDV with HBV Co-infection occurs when a person is exposed simultaneously to serum containing both HDV and HBV. Hepatitis B infection sets in first so that HBsAg becomes available for HDV T ransient and self-limited condition (indistinguishable from acute hepatitis B) R arely progresses to chronic stage; at a rate similar to that of HBV . Vaccination against hepatitis B can prevent against HDV. Super-infection occurs when a chronic carrier of HBV is exposed to serum containing HDV. This results in disease 30–50 days later which may have two phases: Acute phase - HDV replicates actively with high transaminase levels with suppression of HBV. Chronic phase - HDV replication decreases, HBV replication increases, transaminase levels fluctuate, and the disease progresses to cirrhosis and hepatocellular carcinoma (HCC). Mortality rate is much higher (>20%). Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

97. Differences between HDV-HBV co-infection and super-infection   Co-infection Super-infection Definition HBV and HDV infection occurs simultaneously HDV infection occurs to a carrier of HBV Patient status Healthy HBV carrier Risk of development of-     Fulminant >HBV alone >Co-infection   Chronic Rare Much greater   Cirrhosis Rare More   HCC Rare More Mortality Rare >20% Diagnosis 1.HBsAg 2.Anti-HBc (IgM) 3.Anti-HDV (IgM) 4. HDV RNA   1.HBsAg 2.HBeAg 3.Anti-HBc (IgG) 4.Anti-HDV - In acutephase - IgM In Chronic phase- IgG and IgM 5. HDV RNA Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

98. Epidemiology Globally , about 15 million people are infected with HDV (about 5% of 350 million of HBV infected persons). Two epidemiologic patterns have been identified- In endemic areas such as Mediterranean countries - HDV is endemic among persons with hepatitis B and is transmitted predominantly by non-percutaneous means, especially by close personal contact. In non-endemic areas (USA and Northern Europe): Confined to persons exposed frequently exposed to blood and blood products, primarily injection drug users and hemophiliacs who are infected with HBV. I ntroduced into a non-endemic population through drug users or by migration of persons from endemic to non-endemic areas . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

99. Prevention Vaccination for HBV can also prevent HDV infection. General prophylactic measures are essentially same as that for HBV. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

100. HEPATITIS E VIRUS Hepatitis E virus (HEV) causes an enterically transmitted hepatitis. Morphology: HEV is small (30–32 nm size),non-enveloped with icosahedral symmetry. Positive-sense , ssRNA , and a specific antigen (HEV-Ag). Genotypes - HEV has single serotype; however, five genotypes exist in nature, which differ up to 25% in their RNA sequence . Only four genotypes have been detected in humans Genotypes 1 & 2 appear to be more virulent Genotypes 3 & 4 are more attenuated and account for subclinical infections . Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

101. Clinical manifestation Incubation period is about14–60 days ( average 40days ). Most of the patients present as self-limiting acute hepatitis lasting for several weeks followed by complete recovery. Fulminant hepatitis may occur rarely in 1-2% of cases Pregnant women who are particularly at higher risk (20%) of developing fulminant hepatitis. There is no chronic infection or carrier state. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

102. Epidemiology Zoonotic disease - monkeys , cats, pigs, and dogs Transmission - It is feco -orally transmitted via sewage contamination of drinking water or food. Epidemics have been reported primarily from India, Asia, Africa, and Central America; in those geographic areas, HEV is the most common cause of acute hepatitis in this zone. The first major epidemic cof HEV was reported from New Delhi (1995) where 30,000 people were affected due to sewage contamination of the city's drinking water supply following flood in Yamuna river. In India , HEV infection accounts for maximum (30-60%) cases of sporadic acute hepatitis. Though it resembles to HAV, the striking features that differentiate HEV from that of HAV are: Secondary attack rate is rare (1-2%) in HEV, compared to 10-20% in HAV. Age- Young adults (20-40 years age ) Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

103. Laboratory diagnosis HEV RNA (by reverse transcriptase PCR) and HEV virions ( by electron microscopy) can be detected in stool and serum even before the onset of clinical illness Serum antibody detection by ELISA- IgM anti-HEV appears in serum at the same time with the appearance of liver enzymes and indicates acute infection. IgG anti-HEV replaces IgM in 2 to 4 weeks (once the symptoms resolve)and persists for years; indicates recovery or past infection. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

104. Treatment & Prevention Treatment - N o specific antiviral drug available. Prevention- General measures for prevention and containment of infection are the same as described for HAV . China has produced and licensed the first HEV vaccine called ‘ HEV239 ’ using recombinant proteins . However, it is not yet available globally. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

105. HEPATITIS G VIRUS Hepatitis G virus(HGV, also referred to as GB virus C ) was discovered in 1995. It is related to Hepatitis C virus, belongs to family Flaviviridae , under the genus Pegivirus . T ransmitted by contaminated blood or blood products, or via sexual contact. W rongly named as it is not hepatotropic and does not cause hepatitis. R eplicates in the bone marrow and spleen Not associated with any known human disease so far. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers

106. HEPATITIS G VIRUS C lassified into six genotypes, each has its own geographical distribution HIV co-infection- HGV commonly co-infects people infected with HIV (prevalence 35 %) Surprisingly this dual infection is protective against HIV and patients survive longer. Essentials of Medical Microbiology by Apurba S Sastry © 2018, Jaypee Brothers Medical Publishers