Viral Hepatitis. Ahmed Khald & Mostafa Hijazi. Nasser Kaplan

Transcription

1 #6 Viral Hepatitis Ahmed Khald & Mostafa Hijazi 23/11/2015 Nasser Kaplan

2 Hepatitis B Virus (HBV) HBV is hepatotropic Hepadnavirus, its virion is called Dane particle, which is 42 nm double-shelled particles: 1- Outer envelope protein which is the hepatitis surface antigen (HBsAg), over-produced by HBV "surplus/excess" a. HBV produces this Ag more than its need, because of this, in chronic infected patient, the blood antigen level in is very high (10^13 per ml). it is found in two forms : 1- Small, spherical particle which is the predominant one. 2- Filamentous form. Both (1&2) composed of lipid, protein, CHOs and they are NOT infectious. important You have to know that HBVs Ag it is not the cause of the infection,it is just an outer envelope b- In virions the Ag is present in much smaller amount than the patient blood; usually 10^3. 2- Inner protein core = HBcAg, 27 nm in diameter, which encloses viral genomic DNA and the polymerase enzyme. -Other structures are found in HBV: Viral Genome: double-stranded circular DNA Viral polymerase enzyme. HBeAg: it viral protein, it is NOT part of the virion, but it is secreted from infected cells (Hepatocytes) into peripheral blood especially during active viral replication so it is marker/ indicator for viral activity/ replication. viral protein but secreted from infected cells!: the doctor means e Ag is a protein, synthesized by HBV and when Hepatocytes got injured this Ag will leak into peripheral blood.

3 Genetic variation of HBV more than 9 different HBV genotypes, A-I, with considerable geographical variation. HBsAg of all genotypes contains common a determinant, which is main target of protective anti-hbs Ab "= vaccine". Immunity induced by infection or immunization with one genotype crossprotects against infection with others. Variants:- HBV variants HBsAg variants HBcAg variants Polymerase variants which sometimes causes problems in diagnosis and treatment. Stability Doctor said this slide is not important in our exam but you might have a question for the makeup exam: Infectivity lost after autoclaving at 121 C for 20 minutes or dry heat at 160 C for 1 h. Activity maintained after storage at C for at least 6 months & when frozen at 15 C for 15 years. HBV in blood can withstand drying for at least 1 week. Effective chemical disinfectants include: 1- Treatment with hypochlorite (available chlorine) for 10 min; chlorine based disinfectants are the ones most commonly used for environmental disinfection in clinical practice. "very important" 2-2% glutaraldehyde for 5 minutes (previously used to decontaminate Endoscopes but withdrawn due to toxicity. "Effective substitutes include Peracetic acid, hypochlorous acid (superoxidised water) and chlorine dioxide. Don t worry about this"

4 Replication The doctor read this slide, Cellular receptor and mechanism of entry are unknown. HBV needs to uncoat in cytoplasm, and nucleocapsid is transported to nucleus where replication of viral nucleic acid starts. viral polymerase enzyme: multi-functional with reverse transcriptase activity to replicate viral DNA from RNA intermediate. Integration of HBV DNA genome into host chromosome: *can occur during replication cycle. *Position of integration is random. *may be (theoretically speaking) important in mechanism of carcinogenesis "hepatocellular carcinoma ((HCC)". *vs. HIV, integration is NOT essential for replication of HBV. M i c r o Transmission (1) The virus is present in the blood, so it could be transmitted by: - Blood transfusion, blood products and IV drug users. - Sharps and needle-stick injuries: E.g. Lab workers and health care workers: surgeons, dentists, obstetrics and gynecologist. All these exposure prone procedures can cause the transmission of virus from the patient to the doctor and vice versa if the doctor was infected from other patient. (2) Also it is present in body fluids as semen, vaginal secretions so it could be transmitted by (sexual; both homo- and hetero-sexual and vertical from mother to child during birth; transplacental infection is rare unless maternal viral load is very high).

5 (3) It could be transmitted by saliva (close contact between family members, siblings, peers and residents in institutions and biting and scratching, sharing of household tools as toothbrushes and razors). it can also enter abraded skin (intact skin is resistant to HBV penetration), or mucous membranes. HBV infection sequels It is worldwide infection.1/3 of population is infected and 350 million are chronically infected. Of these, 15-40% will develop serious sequels. Doctor notes (imp) - Adults -9o% will recover. - 1% will have Fulminant HBV. - 10% will RESULT in chronic : - 5% will develop chronic inactive hepatitis B and the rest will develop chronic active hepatitis which will lead to liver failure+ HCC+cirrhosis Children - less than 10% will recover. - 90%( 30%-50% males, 10%- 20%females) will have chronic active hepatitis B in female there will be chronic active which lead to transmession to the child,cirrhosis,liver failure or hepatocellular carcinoma(hcc) in adulthood. note/ when we talk about liver failure : falminent following acute infection or end stage liver failure following chronic HBV infection

6 Acute infection of HBV incubation period months, relatively long. Asymptomatic, esp. in children. Prodrome: malaise, anorexia, weakness, myalgia, nausea and vomiting. Clinical indicators of hepatitis: jaundice, Right upper quadrant abdominal pain, pale stool and dark colored urine." I think this is because bilirubin will be excreted in the urine rather than feces." Paradox: patient is physically better when jaundice appears. Lab biochemical indicator of hepatocellular damage: increase ALT levels before onset and after resolution of clinical jaundice. Immunological sequelae: In some cases, circulating immune complexes cause arthralgia, urticarial or maculopapular skin rash, polyarteritis, nodosa or glomerulonephritis. Chronic infection of HBV It is indicated by continued presence of HBsAg and HBV DNA in peripheral Blood >6 months. High incidence in very young (remember in the chart 90% of infected children have chronic hepatitis) and immunocompromised patients. In neonate, occurs in presence of maternal anti-hbc and HBeAg, which can cross placenta and this will lead to tolerance. *** Four stages of chronic hepatitis: 1- Immune (immunological) tolerance phase 2- Immune (immunological) clearance (control) phase 3- chronic inactive HBV infection 4- HBeAg negative chronic hepatitis - through emergence of viral variants/ mutants" genetic mutations"

7 Stages of chronic hepatitis 1- Immune tolerance phase (viral replication without any symptoms) Patients are highly infectious, mostly young children and immunocompromised. Lab: HBeAg positive, because we have very high level of viral activity/ replication this will lead to viraemia with characteristic very high HBV DNA, normal ALT & little evidence of necroinflammation or fibrosis on liver biopsy. Explanation: Let's assume that we have patient got infected with hepatitis B virus, what will happen? The virus starts to replicate in a very, very high rate and will start a little necrosis and fibrosis in the liver, so the immune system will not be activated "will tolerate this situation" so we will call this stage tolerance stage: In the blood we will find: 1- Normal ALT why? Bcz we don t have cellular injury yet. 2- High HBe Ag and HBV DNA why? Bcz the virus is active/ replicates "viraemia ". 3- No Abs why? Bcz immune system is in tolerance stage. 2- Immune clearance phase (occurs when immune tolerance is lost) Patients are typically in early adulthood infected at young age. differential diagnosis is acute hepatitis due to similarity in symptoms & presence of low levels of IgM anti-hbc."plz know that the antibodies are against hepatitis B core". Clearance stage,,,abs against the core. Lab: HBeAg positive, slightly lower level of HBV DNA,fluctuating levels of ALT and evidence of moderate to severe liver necroinflamamation and rapid progression of fibrosis. Prognosis: The longer the duration, the more is the resultant liver damage.

8 Explanation: Now immunity decides to stop this tolerance stage and to defense against this virus so we will call it clearance stage The war will start btw x immunity and HBV so in the blood we will find: 1- From the immune system: antibodies against hepatitis B core (IgM anti-hbc Ag) "why the core not the envelope? Bcz the immune system wants to save the time so always remember it attacks the virus from inside to outside from the core to the envelope ". 2- The virus is still trying to replicate, what does this mean? We have positive HBe Ag and HBV DNA (high but lower than stage one). 3- Moderate to severe necrosis and fibrosis (fluctuating levels of ALT). 3- Chronic inactive HBV infection (occurs with successful immune clearance of active HBV infection) Patients: asymptomatic but most remain HBsAg positive. tend to have more favorable long-term outcome, Traditionally they used to call patients in this stage Healthy HB carriers but this is false sense of security, as 10-20% may revert to active infection (reactivation) or change to phase (4) so life-long follow-up is necessary. Lab: Sero-conversion from HBeAg to anti-hbe. HBV DNA levels very low or undetectable. ALT levels normalize. Explanation: The virus will become inactive so we will call it inactive chronic hepatitis No injury and no replication so what we will find in the blood? 1- immunity wins anti-hbe ag >>>> HBe ag 2- no replication low HBV DNA 3- no injury.normal ALT 4- the virus is inactive so the most Ag in the blood is HBsAg - the virus is still in the body so x is still infected but asymptomatic we can't say he is healthy and we have to follow him because at anytime the virus can be reactivated or win (stage 4)

9 4- HBeAg negative chronic HB - through emergence of viral variants/ mutants In some patients, after sero-conversion from HBeAg to anti-hbe, HBV variant emerges which is HBeAg negative but viral activity/ replication remains i.e. active disease which may lead to cirrhosis and HCC. Lab: periodic fluctuating levels of HBV DNA (moderate levels) and ALT. differential diagnosis : (3) inactive phase due to fluctuating course. (Remember, (4) is active disease). Explanation: The immunity wins by anti- HBe ag so the virus makes mutation "variant ", this new variant is active but without HBe ag so the Abs can't find it "this stage is called HBe ag negative chronic hepatitis through virus mutation " 1- no HBe ag (but active ) 2- no need for anti HBe ag so it is low 3- active cell injury,cirrhosis and HCC 4- periods of replication /tissue injury.so we have periodic fluctuating levels of HBV DNA (moderate) and ALT. Important We have fluctuating periods and negative HBe ag.. in the period of low DNA and ALT u may think this stage 3 bcz in this stage DNA is low and HBe ag is also negative so stage 3 is deferential diagnosis,,, what is the difference? Stage 3 virus is inactive so there is no disease, no tissue injury Stage 4 virus is active, there is disease..

10 Outcomes 0.5% per year of patients with inactive chronic HB will clear HBsAg (i.e. with Resolved HBV infection). *Indicator of past HBV infection: presence of anti-hbc, with or without anti- HBs. *Risk of HCC is significantly reduced but NOT completely eliminated, especially in older patients or patients with liver cirrhosis. In most cases, HBV is NOT completely cleared and reactivation can occur in immunosuppression as after organ transplantation or treatment with immunosuppressive drugs. In some patients, HBV DNA is persistently detectable in Peripheral Blood in absence of HBsAg = Occult HBV infection. Note / the doctor said that you must be familiar with these terms 1- Resolved HBV infection 2- Occult HBV infection 3- Healthy HB carriers

11 SUMMRUY : 1) +HBs /+DNA /+HBc.. infected (high HBe/ active ) 2) HBs/+DNA.. occult infection 3)+AB against the core or/and the envelope without the presence of any antigen or DNA "cure/past infection /memory cells and adaptive immunity" 0.5% About the chart the doctor said that it summarize the whole lab markers that we mention Other risk factors of cirrhosis older age or longer duration of infection. infection with HBV genotype C. high level of HBV DNA.( that means there is A viral replication) C genotype of HBV is risk factor for cirrhosis C.cirrhosis and HCC heavy alcohol consumption & concurrent infection with HCV, HDV or HIV. Hepatocellular carcinoma (HCC) focus on the highlight Worldwide, 80% is caused by chronic HBV infection that is why highest rates of HCC are in endemic areas and infection at very early age. Risk factors: prolonged presence (>40 years) of HBeAg, high levels of HBV DNA, infection with HBV genotype C, presence of core promoter variants, co-infection with HCV, male gender, family history, older age & cirrhosis. Only 5% of patients with cirrhosis develop HCC vs % of patients with HCC have underlying cirrhosis this indicate that still there is proportion of HCC occurs in absence of cirrhosis. Integration of viral DNA is possible mechanism of carcinogenesis.(theory) HCC can be prevented by vaccination. CIL (clinical immunology lab ) diagnosis There is a wide range of tests for HBV Ags and Abs detection, using immunoassays based on enzyme reactivity (EIA) or chemiluminesence (CLIA). (don t worry about the names of technics) HBV DNA (viral load) quantitation in serum or plasma using real time PCR. "currently ". Standard screening test: HBsAg in serum as an indicator of current HBV infection. " this is standard one". Standard..s antigen

12 Lab indicators (1) Acute infection " Doctor notes, in acute hepatitis B infection,the first thing to appear will be viral DNA followed by HBV surface antigen,then the patient will have clinical symptoms. the window theory is a laboratory defined theory of lacking certain indicators and existence of others,in which the surface viral antigen will be positive but the viral itself "the DNA" will be positive. at this time, IgM anti-hbc is present,it indicates recent primary infection. the HBe antigen will be produced as indicator of viral activity and replication,it will be after HBs antigen. so the first one is DNA,second one is HBs ag, then HBe ag. IgM anti-hbc is transient response in high titre, (it is indicator of recent acute infection.) The doctor said that there will be a question about the present or absent lab marker And he will not ask which one apper first or next

13 (2) Chronic infection In laboratory diagnosis: IgM anti-hbc [anti-hepatitis B core]is replaced with IgG anti-hbc HBeAg: detectable during phases (1) & (2) & replaced by anti-hbe in phases (3) or (4). Remember for infectivity, it is an indicator of activity and replication so the patient will be sick. HBV DNA (viral load) levels: which is quantitative by real time PCR persistently low in phase (3). Show fluctuating moderate to high levels in phase (4). The doctor said that he does not have time to read all the slides So please Focus on the highlight Treatment: Liver failure (fulminant [complicated acute] or end stage [complicated chronic]) transplantation. Acute infection: which is presented clinically and laboratory while usually needs supportive treatment. Immune tolerance phase: antiviral treatment NOT used. Close monitoring at 3-6 monthly intervals. Chronic inactive infection: antiviral treatment NOT needed. Chronic infection: antiviral treatment needed to suppress HBV replication & prevent progression of liver disease into more serious consequences like cirrhosis, liver failure & HCC. AniviralTreatment include: 1- Long acting pegylated a-ifn (PEG-IFN) PEG-IFN = it is alpha interferon undergone pegylation. Pegylation is: IFN-a covalently attached to polyethylene glycol polymer chains. Pegylation prolongs half-life of interferon that s why dosing will be restricted to once weekly injection. (Pegylation will give longer half-life for interferon) First-line treatment for patients without cirrhosis. ( giving it to cirrhosis pt. >>hepatic failure Effects: antiviral, anti-proliferative &immuno-modulatory. Duration of administration: weeks. Limited efficacy: seroconversion from HBeAg to anti-hbeoccurs in ~30%. Side effects (you have to take them into consideration): common & includes Flu-like symptoms, neutropenia, thrombocytopenia, autoimmune thyroid disorders &psychiatric symptoms as depression. Exacerbation of hepatitis is common & often favorable indication of subsequent response (but in patients with existing cirrhosis hepatic failure). That s why it is only used in patients without cirrhosis important to remember

14 [You have to know that if you are treating your patient with pegylated alpha interferon you might exacerbate the hepatitis which is a common side effect]. 2- Long-term suppression with nucleoside or nucleotide analogues[the Dr will not talk about them but please have a look at them- there will be a question for makeup exam Control Method & prevention of HBV infection A- Modification of risk factors / behavior: 1- Implementing infection control policies (Health Care Workers & 2- patients). 3- Screening of blood for transfusion & organ donors for transplantation. Which is a common current practice everywhere nowadays. 4- Reducing needle sharing among injecting drug users. Not common in our country 5- Avoiding unprotected sexual contact by use of condoms. B- Immunization: passive & active. (1) Passive immunization - (HBIG) Hepatitis B Immunoglobulin Preparation: from donors with high titres of anti-hbs.

15 Doses: of IU in 2-4 ml by IM. Administration: (IM) As soon as possible after exposure &before 48 h; second dose 4 weeks later to vaccine non-responders (because some people who have been toxinated may not respond to the vaccine). Efficacy: NO absolute protection but ~76% efficacy. (may not result in absolute protection because the efficacy is %) Indications: (Dr. said you should read it yourself. Slide 28) 1- After accidental exposure if NOT vaccinated or vaccine non-responder: in needle-stick injuries & NOT vaccinated combination of HBIG + course of active immunization into different body sites. (2) Active immunization (currently available vaccines) Preparation: (Genetic Engineering) by cloning HBsAg gene in yeast cells Administration: IM. Schedule: recommended 3 doses at 0, 1 & 6 months. (Shorter schedules may be appropriate in some circumstances). Side effects: NO major side effects; local swelling & pain with slight fever. [VERY SAFE VACCINE] Seroconversion rate (this is important) After receiving the vaccine, it is influenced by number of factors: 1- Age & sex (most important): (>95% in young women vs. 80% in older men). 2- Immunosuppression: only 50-60% in pts on maintenance dialysis. 3- Vaccine injection into fat reduces seroconversion recommended into deltoid muscle of upper arm. (So it should be injected in muscular sites like deltoid) Duration of response to vaccine o Variable & dependent on titre of anti-hbs achieved after completion of course. o Post-vaccination anti-hbs level should be>10 miu/ml is (protective). o However if,anti-hbs level 2-3 months after third dose <100 miu/ml booster dose to ensure higher level of protection. o NO response is detected (<10 miu/ml) course of 3 further doses (give the course again). o Vaccine non-responders (fail to develop immunity after 2 vaccine courses); NOT protected need prophylaxis by passive immunization with accidental exposure.

16 Who should be immunized? WHO recommendation: universal childhood vaccination against HBV. If NO universal vaccination programme groups targeted for HBV vaccination: ( the doctor didn t read the groups) Babies of chronically infected mothers. Injecting drug users. Close family contacts & sexual partners of case. Pts. needing frequent transfusions &/or blood products. Pts. with chronic renal failure. Pts. with chronic liver disease. Inmates of custodial institutions. (Prisoners or people in mental institutions) Long stay travelers to endemic countries. Hepatitis D virus (HDV, Delta agent) smallvirus, enveloped,containing single, small, circular RNA genome with internal Delta (d) Ag enveloped by HBsAg. cannot replicate without assistance from HBV. Clinical features & pathogenesis HDV can only infect simultaneously with HBV (co-infection) or as superinfection of patients with chronic HBV infection. Co-infection has better prognosis than superinfection. Superinfection in severity of chronic hepatitis with risk of cirrhosis, liver failure& HCC. Clinical Immunology Lab Diagnosis: Tests available for HDV Ag, Ab& RNA. Co-infection: initial Ab response to HDV infection is IgM. Superinfection: 1-HBs Ag titer may decrease or disappear diagnostic confusion 2-HBV DNA/ viral load levels may decrease false assurance that HBV infection is NOT active if HDV super-infection is NOT recognized

17 Typical serological profile (markers) of simultaneous HBV & HDV coinfection Typical serological profile (markers) of chronic HBV with HDV super-infection Epidemiology >8 different genotypes with considerable geographical variation. IV drug use is important factor. Immigrants from regions endemic for both HBV & HDV. Treatment Prolonged course of pegylated interferon: only proven treatment. NO benefit in adding ribavirin or nucleos(t)ide analogues against HBV. Control HBV vaccine will prevent HDV co-infection, but there is NO means of protectingagainst HDV superinfection. (the same control measures applied to HBV)

18 Picornaviruses small (Pico) RNA viruses Hepatitis A is a member of picorna virus Enteroviruses you don t need to worry about them. This following table is to know that there is a long list of serotypes of enterovirus. Enteroviruses have numbers from is Family picornaviridae consists of 12 genera of which: enterovirus (including the former rhinovirus genus), parechovirus&hepatovirus genera causing variety of human diseases. the hepatovirus (hepatitis A).So it is an enterovirus with pico (small) RNA. Hepatitis A virus (HAV) Hepatovirus genus consists of HAV as its only one specie. Cosmopolitan; worldwide distribution -causing sporadic cases&outbreaks called infectious hepatitis. Transmission Infectious dose: very low infectious dose of virus particles. Faecal-oral route. Outbreaks (important) : associated with food especially raw or undercooked shellfish. sewage outlets Only few infections recognized after blood transfusion (exception you don t need to worry about). IP: 3-6 weeks.

19 Clinical Picture: Mild illness.-(shorter incubation period ) Prodrome: nausea, malaise >> Non-specific Fulminant hepatitis & liver failure are rare. NO chronic infection, CIinical ImmunologyLab Diagnosis: Virus in stool samples by EIA (Enzyme Immunoassay) or RT-PCR (revesetranscriptace PCR). specificigmab in serum after onset of symptoms. IgGAb usually persists for many years & isa useful indicator of immunity. Treatment Supportive NO specific antiviral drugs. Severe cases of fulminant liver failure (If happens) transplantation. Vaccine Highly effective & immunogenic. Formaldehyde-inactivated vaccine (inactivated virus). Unlike HBV vaccine -clonning

20 Primary course: (the doctor didn t read it) Two doses (or, more recently, single dose) I/M good levels of neutralizing Ab which persists for =10 years. Preferred to human normal Ig (HNIG)for frequent travelers, for those with potentialoccupational exposure & to protectcontacts of cases. HNIG: is another name for immunoglobulin. Obtained from the blood of human donors. It contains general antibodies that are not specific to a particular infection. Hepatitis C virus (HCV) Discovered in 1989, was very important causative agent of posttransfusion (non-a,non-b hepatitis).(after blood transfusion when they didn t find a marker for either A or B so it HCV) Members of Flaviviridae (greatest similarity with flaviviruses). Small round particles, enveloped with single stranded RNA genome of positive sense. Problematic to culture in vitro. (No in vitro culturing) The doctor said that you need to remember that: Hbv>>hepadnavirus Hav>>piconavirus Hcv>>flaviviridae The table is Not required

21 Human pegivirus (HPgV, originally described as GB virus C or hepatitis G virus) The doctor read the slide but he said (don t worry about HGV) Widely distributed in humans. Originally thought to be involved in post-transfusion & chronic hepatitis of unexplained etiology BUT infection appears to be entirely asymptomatic, despite being persistent in significant proportion of infected pts. Its genome shows number of similarities to that of HCV. HCV Genetic variation Substantial differences in nucleotide sequences >or=6 HCV genotypes with variable geographical distribution &number of subtypes. Virus stability HCV is inactivated by exposure to chloroform, ether & other organic solvents and by detergents. Dry-heat treatment at 80 C or wet-heat treatment at 60 C,organic solvents (n-heptane) & detergents efficiently remove HCV infectivity (used in preparations of plasma factor VIII & IXconcentrates used to treat haemophiliacs). (don't worry about this too much. The doctor said) Epidemiology (at-risk groups for parenteral blood-borne exposure) Cosmopolitan - Worldwide distribution Injecting drug users (IDUs). Blood transfusion. Transplant recipients, hemodialysis pts. Tattooing & acupuncture. Use of unsterilized needles Sexual contact. Mother-to-child.

22 Clinical Picture: -Frequently persistent & slowly progressive with long asymptomatic carrier phase cirrhosis, liver failure or HCC. -This is a flowchart showing the outline of infection of Hepatitis C virus. It might lead to hepatic failure or HCC. 1- Acute hepatitis Asymptomatic without jaundice, with only 25-50% pts clearing the infection spontaneously & remainder become chronically infected. Development of abnormal LFTs (as ALT). Jaundice may develop, but more usually symptoms are non-specific as fatigue, anorexia & nausea. Viraemia detected in early stages, at same time or slightly earlier than abnormal ALT levels, while seroconversion for Ab delayed for weeksmonths after onset.

23 (2)-Chronic hepatitis Frequency id 50%-70% Persistent & progressive, with fluctuating or continuously abnormal ALT levels. Viraemia is invariably detected with NO correlation between level of viraemia & severity of liver disease, ALT levels or other associated biochemical abnormalities. Progress to cirrhosis (after years with infection of HCV) & liver failure is almost invariably very slow (it is faster with risk factors as alcohol ingestion, older age &immunodeficiency and aggressive in immunosuppressed organ transplant recipients & in pts. with inherited immunodeficiency states). HCC is a frequent complication in chronic infection with Hepatitis C virus. 2- Extra hepatic Manifestations In minority of pts. Inc. certain types of vasculitis & GNitis(glomerulonephritis) caused by immune complex deposition. Associations with? Sjogren s syndrome, essential mixed cryoglobulinaemia & membranoproliferative GNitis type 1.

24 Clinical Immunology Lab Diagnosis: (you need to read this on your own. The doctor said) 1- Direct detection of Ab to all HCV genotypes: Used for general screening. By 2 stage of laboratory detection: (1) ELISA format for initial testing repeatedly reactive (positive) samples retested by: (2) Second ELISA in different format or by supplementary assay. Does NOT allow distinction between past, cleared infection & current infection. But it will indicate that there is a sort of infection. 2- Direct detection methods of viral genome or antigen: (1) genomic RNA (RT-PCR, real-time PCR quantitation of titre; viral load only reliable method of monitoring response to treatment) or (2) direct detection of viral Ags by (ELISA) method. Used for effective Dx in acute hepatitis, in immunosuppressed pts with NO detectable Ab response & to Identify and differentiate between current vs. past infection. This is why we use the direct detection of either genomic RNA or Antigen. Treatment Current standard treatment for chronic HCV infection: Pegylated interferon-a & oral Ribavirin (RBV). There is 3 patterns of response to treatment are mentioned by quantitative PCR for detection of viral RNA : 1) Non-response 2) Response but with relapse after cessation of treatment. 3) Sustained virological response in which (SVR; viral RNA NOT detectable 6 months after end of treatment course; cure). ~50% of patients achieve SVR. Response to treatment varies signifycantly between HCV genotypes due to unknown mechanism. Poor response to treatment: 1) Immunosuppression 2) Co-infection with HIV-1 3) High viral loads 4) Decompensated HCV cirrhosis.

25 Prevention Screening of blood donors. Education awareness. Hepatitis E virus (HEV) Classified as Hepevirus. Non-enveloped, single-stranded positive sense RNA single serotype with strong cross-reactions among the four known human spp (HEV-1, -2, -3 & -4). Epidemiology Faecal-oral transmission Endemic in undeveloped areas, may be by person-to-person transmission or in non-human animal reservoir. >50% of sporadic cases will be caused by HEV. Large water-borne outbreaks.(important) Clinical Picture: IP: days (average 40 days) Acute hepatitis mostly in years old with anorexia, fever, abdominal pain, nausea & vomiting (nonspecific sign and symptoms). Urine darkens & stools lighten. LFTs show hepatocellular damage. Jaundice. Younger pts.: mostly mild & anicteric incubation period up to 2 months. mortality rate: Overall 1-3% (Low mortality). However, it can reach 15-25% in third trimester of pregnancy due to severe form with fulminant hepatitis.

26 Lab Dx IgM & IgG Abs measurement. RT-PCR to detect viral RNA. Rx NO specific Rx. Ribavirin is effective in chronic infection. Prevention Safe clean water. High standards of food hygiene. NO passive immunization or vaccine.