Viral hepatitis

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  • For half of all identified HAV cases in 2007, no risk factor was identified. 1 In pregnant women, acute HAV infection may be associated with maternal complications and preterm labor. Despite low endemic rates and successful vaccinations of at-risk populations in the United States, unvaccinated children acquiring HAV infections abroad can serve as reservoirs of the virus upon return to the United States, even while remaining clinically asymptomatic themselves. Nearly 40% of children younger than age 15 years with HAV had international travel as a risk factor in 2004
  • MSM Use of injectable drugs / IVDU Overcrowding Non-enveloped, heat-, acid-, and ether-resistant RNA virus Replication is limited to the liver
  • Children <6 years of age typically are asymptomatic . Symptoms, if they do occur, do not include jaundice. In older children and adults , the majority of patients present with symptoms that last less than 2 months and 70% of adults experience jaundice. Peak viral shedding precedes the onset of GI symptoms in adults. In young children, shedding can occur for months following diagnosis. 2 Because children are often asymptomatic and will shed the virus for long periods of time they can serve as a reservoir for the spread of HAV.
  • Children <6 years of age typically are asymptomatic . Symptoms, if they do occur, do not include jaundice. In older children and adults , the majority of patients present with symptoms that last less than 2 months and 70% of adults experience jaundice. Peak viral shedding precedes the onset of GI symptoms in adults. In young children, shedding can occur for months following diagnosis. 2 Because children are often asymptomatic and will shed the virus for long periods of time they can serve as a reservoir for the spread of HAV.
  • Hepatitis A Vaccine, IgG for short term Px, all persons at risk
  • HAV RNA is detectable in the serum for an average of 17 days before peak ALT levels and can persist for an average of 79 days after the onset of symptoms In some patients, serum HAV is detectable for more than a year.
  • Hepatitis A is transmitted via the fecal–oral route. Transmission is most likely to occur through travel to countries with high rates of hepatitis A, poor sanitation and hygiene, and overcrowded areas. Hepatitis A causes an acute, self-limiting illness and does not lead to chronic infection. There are three stages of infection: incubation, acute hepatitis, and convalescence. Rarely, the infection progresses to liver failure. Treatment of hepatitis A consists of supportive care. There is no role for antiviral agents in treatment.
  • HELLP syndrome
  • In the United States, the introduction of hepatitis A vaccination programs among children from high-incidence states has resulted in a >70% reduction in the annual incidence of new HAV infections and has shifted the burden of new infections from children to young adults.
  • Although hepatitis A is rarely bloodborne, several outbreaks have been recognized in recipients of clotting-factor concentrates Adults  — The Advisory Committee on Immunization Practices ( ACIP ) of the Centers for Disease Control and Prevention ( CDC ) has recommended hepatitis A vaccination of adults who have any of the following medical , occupational , or lifestyle risk factors. Persons with clotting-factor disorders or chronic liver disease Men who have sex with men or users of illegal drugs Those with close personal contact (eg, household contact or regular babysitting ) with an international adoptee from a country of high or intermediate endemicity during the first 60 days following arrival of the adoptee in the United States Persons working with hepatitis A virus infected primates or with HAV in a research laboratory Persons traveling to countries with high or intermediate endemicity Any person wishing to obtain immunity Children  —   Hepatitis A vaccination was incorporated into routine childhood vaccination schedule in 2006. Previously, HAV vaccination had been recommended routinely only in some regions within the United States, where the incidence of hepatitis A is higher than the national average. These relatively high-risk states include Arizona, Alaska, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, and Washington. Such programs have been highly effective in reducing the incidence of hepatitis A among children and adults and (combined with extended safety data) provided the impetus for broadening the vaccination recommendation Passive Immunization: IgG Pre -exposure— travelers Post exposure (w/i 14 days ) Active Immunization Persons at Increased Risk Travelers MSM Drug users Chronic liver disease Communities with high rates of Hepatitis A
  • INACTIVATED HEPATITIS A VACCINES —   HAVRIX (Smith-Kline Beecham) was the first hepatitis A vaccine  (HepA vaccine) licensed for use in the United States and approved by the Food and Drug Administration (FDA) in 1995 [ 4 ]. HAVRIX is a purified, formalin-inactivated vaccine prepared in a human cell culture line. The vaccine is manufactured from the HM 175 virus strain , adapted to grow in human diploid MRC-5 cells , with formaldehyde inactivation performed at a concentration of 250 mcg/mL at 37ºC for 15 days . The antigen content of the vaccine is measured by a specific and accurate ELISA (enzyme-linked immunosorbent assay) with vaccine po tency expressed as ELISA units (EL.U) of antigen. The HAV virions are subsequently adsorbed onto 0.5 mg/mL aluminum hydroxide  adjuvant in isotonic buffered saline containing 0.5 percent 2-phenoxyethanol as a preservative. A second purified, formalin-inactivated vaccine using the CR326 viral strain (VAQTA, Merck Sharp Dohme) became available in the United States in 1996 The two vaccines had equivalent immunogenicity , but fewer side effects (typically local reactions ) were observed with VAQTA . However, VAQTA vaccine was recalled in the fall of 2001 when it was discovered that the antigen content in some prefilled syringes was below the established minimum specification. Thus, patients who received this vaccine may not be adequately protected . Such patients should be either revaccinated with an alternative vaccine or tested for evidence of serologic immunity
  • The change to the use of the vaccine is advantageous as vaccination confers the benefit of long-term immunity against HAV. Immunogenicity  —  The majority of studies demonstrate almost a 100 percent seroconversion rate (defined as an antibody concentration of >20 mIU/mL measured by ELISA) after a primary vaccination course in both adults and children [ 2,8-12 ]. Furthermore, the antibody concentration achieved with the HepA vaccine is much greater (nearly 15 times in one report) than the concentrations reached with protective doses of immune globulin (IG) [ 13 ]. The response is also much more long-lasting as illustrated in a study which compared the immunogenicity of the inactivated HepA vaccine, in single and booster doses, with IG administered once as an intramuscular injection [ 14 ]. With the vaccine, seropositivity by radioimmunoassay was seen in 73 percent at week 2, 100 percent at week 5, and 100 percent at week 24. The comparable values for seropositivity after IG were 100 percent at week 1, 10 percent at week 12, and 0 percent at week 20. Another study evaluated the reactogenicity, immunogenicity, and long-term antibody persistence after the administration of inactivated HepA vaccine (720 EL.U) to adults [ 15 ]. The vaccination schedule consisted of primary immunization at baseline and one month, followed by a booster injection 6 to 12 months following initial vaccination. The subjects were followed up to 36 months, and geometric mean antibody titers (GMT) against HAV were monitored. The GMT increased with each dose of the vaccine with a peak in antibody titers occurring at seven months. There was a rapid decline in titers (by 61 percent) between 7 and 12 months and a slower decline beginning at 12 months (14 percent). Based upon these observations, the investigators devised a mathematical model to predict antibody persistence over time. Assuming a constant rate of decline in antibodies to HAV, the authors estimated that the duration of protection when antibody levels are >20 mIU/mL ( a level conferring immunity ) is between 20 and 30 years . An anamnestic response has been demonstrated empirically up to 12 years after vaccination [ 16 ]. Thus, there is no evidence that a HepA booster vaccination after a full primary vaccination is needed in healthy individuals, although there are as of yet no long-term data following the two-dose vaccine regimen used in clinical practice [ 17 ]. The effectiveness of the HepA vaccines is underscored by the decline in HAV cases since their introduction
  • Dosing regimens  —   For HAVRIX , primary immunization in children and adolescents (12 months through 18 years) consists of a single dose of 720 EL. U ., in 0.5 mL and a booster dose (720 EL. U. in 0.5 mL) any time between 6 and 12 months later. In adults, immunization consists of a single dose of 1440 EL. U. in 1 mL and a booster dose (1440 EL. U. in 1 mL) anytime between 6 and 12 months later For VAQTA , primary immunization in children and adolescents (12 months through 18 years) consists of a single 0.5 mL (~25 U ) dose and a booster dose of 0.5 mL (~25 U) 6 to 18 months later. For adults 19 and older, immunization consists of a single 1.0 mL (~50 U) dose and a booster of 1.0 mL (~50 U) 6 to 18 months later. It is good practice to use the same brand of vaccine to complete a course . If this is not possible , products for booster dose are interchangeable (eg, Vaqta can be used for booster dose following primary dose of Havrix and vice versa). The change to the use of the vaccine is advantageous as vaccination confers the benefit of long-term immunity against HAV. Decompensated cirrhosis:     HAV vaccination has been recommended for patients with chronic liver disease because of the increased morbidity and mortality associated with acute HAV in such patients. However, patients with advanced liver disease may have a diminished response to HAV vaccination. An illustrative study compared seroconversion in 35 patients with decompensated disease with 49 patients with compensated chronic liver disease [ 18 ]. One month after the booster dose, seroconversion rates were significantly lower in those with decompensated disease (66 versus 98 percent). Median serum antibody concentrations were also lower. On multivariate analysis, Child-Pugh class B or C was predictive of a lower response rate. These data suggest that vaccination should ideally be accomplished before the development of advanced disease. Safety : More than 188 million doses of hepatitis A vaccine  have been sold worldwide since 1995 [ 19 ]. The most common adverse events are fever , injection-site reactions , rash , and headache . While serious adverse events (including Guillain-Barre' syndrome, elevated liver biochemical tests, and idiopathic thrombocytopenic purpura ) have been reported, their relationship to vaccination is unclear.
  • Guillain-Barré syndrome ; a nervous disorder in which, after a non-specific infection , demyelination of the spinal roots and peripheral nerves takes place, leading to generalised weakness and sometimes respiratory paralysis. multiple sclerosis: a nervous disease which gets progressively worse, where patches of the fibres of the central nervous system lose their myelin , causing numbness in the limbs and progressive weakness and paralysis . erythema multiforme: the sudden appearance of inflammatory red patches and sometimes blisters on the skin Furthermore, incidence of serious adverse events in the vaccinated population did not differ from the incidence in nonvaccinated populations. It is important to note that more than 65 million doses of the vaccine have been administered and despite routine monitoring for adverse events, there are no data to suggest a greater incidence of serious adverse events among vaccinated people compared with nonvaccinated. The vaccine is considered safe.
  • Twinrix  —   Similar results were obtained in two clinical trials which evaluated a combined hepatitis A/ hepatitis B vaccine  [ 26,27 ]. The vaccine contained 720 EL.U . of hepatitis A antigen and 20 mcg of hepatitis B antigen absorbed on 0.5 mg of aluminum hydroxide  as an adjuvant. Seroconversion rates were consistently high , the vaccine was well tolerated, and there were no appreciable adverse effects . A combination vaccine consisting of HAVRIX and Energix-B (Twinrix, GlaxoSmithKline) is commercially available LIVE ATTENUATED VACCINES  —   The use of attenuated live HepA vaccines has been evaluated in both animals and humans . One report described the experience in China , where clinical trials began in 1987 [ 31 ]. Over the next few years, 3089 adults and 3072 children were inoculated with the vaccine. The following results were noted: Seroconversion occurred in 95.6 percent of volunteers within three weeks, similar to naturally acquired immunity. Subjects studied up to three years had persistence of the antibody in serum samples. There were no major side effects, and elevations in serum aminotransferases were not noted. Live attenuated HAV was found in the stools of 75 percent of persons who had received the vaccine; however, transmission of HAV from vaccinees to seronegative persons who were not administered the vaccine did not occur. Thus, this type of vaccine is well tolerated and highly immunogenic . However, with the recent licensing of the inactive HepA vaccines , the use of a live attenuated vaccine will probably be limited.
  • Ig is available both as an intravenous (IV) and IM injection but for HAV exposure, only the IM is used. If given to infants or pregnant women, the thimerosal-free formulation should be used. Postexposure summary and recommendations  —   The following are the recommendations from the Advisory Committee on Immunization Practices [ 57 ]. Persons who have been exposed recently to hepatitis A and who have not previously received hepatitis A vaccine  should be administered a single dose of single- antigen hepatitis A vaccine or immune globulin (IG) (0.02 ml/kg) as soon as possible. For healthy persons aged 12 months to 40 years, single-antigen hepatitis A vaccine at the age-appropriate dose is preferred. (See 'Indications'  above.) For children aged <12 months, immunocompromised persons, persons who have had chronic liver disease diagnosed, and persons for whom vaccine is contraindicated, IG should be used.
  • HAV vaccination or prophylaxis with Ig is recommended for travelers to countries with high endemic rates of HAV. Serious adverse events are rare. Anaphylaxis has been reported in patients with Ig A deficiency. Patients who had an anaphylaxis reaction to Ig should not receive it. There is no contraindication for use in pregnancy or lactation. CONTRAINDICATIONS  FOR MMR Vaccine — Certain patients should not receive MMR or MMRV vaccines because they are live virus vaccines : Women who are pregnant should not receive MMR vaccine; women who do receive this vaccine should avoid becoming pregnant for 30 days after receipt of MMR to avoid possible risk to the developing fetus. MMR vaccine should not be administered to patients who are receiving acute high-dose steroid therapy or long-term maintenance doses of prednisone  of ≥20 mg per day . Individuals with known allergy to neomycin  should not receive MMR vaccine because trace amounts of neomycin are contained in the MMR vaccine. Those with known allergy to eggs can receive MMR vaccine; the risk for anaphylaxis after MMR vaccination is extremely low, even in persons with severe egg allergy symptomatic HIV-infected patients with severe immunosuppression .
  • In the first study, the authors compared no intervention to five possible strategies for HAV prevention. The prevention strategies included: Vaccination with the two-dose primary course (HAVRIX 720) Vaccination with the one dose primary course (HAVRIX 1440) Screening for anti-HAV, followed by HAVRIX 720 Screening for anti-HAV, followed by HAVRIX 1440 Administration of IG The investigators concluded that the optimal strategy varied with the estimated travel history: In persons who will travel only twice in a 10-year period for a short duration , passive immunization with IG is the most cost-effective treatment. If the travel frequency surpasses three times in a 10-year period or the length of stay exceeds six months , the HepA vaccine is the more cost-effective strategy. Prevaccination antibody screening is only justified in older travelers , those from countries in which HAV is endemic (average prevalence of immunity of over 30 percent), or those with a history of jaundice . Either the deltoid or gluteal muscle may be used. In children younger than 24 months of age, Ig can be given in the anterolateral thigh muscle Ig can be given concomitantly with the HAV vaccine. Although the antibody titer will be lower than if the vaccine were administered alone , the response is still protective. However, Ig can interfere with the response of other vaccines and should be delayed.
  • Simultaneous administration with other vaccines — It would be advantageous to use a vaccination schedule allowing the simultaneous administration of several required vaccines. The inactivated HepA vaccine can be given concurrently with the vaccines for diphtheria , tetanus , pneumococcus , oral typhoid, cholera , Japanese encephalitis, rabies , or yellow fever without adversely affecting immunogenicity or safety [19-21]. It is recommended that the injections be given at different sites . The efficacy of the simultaneous administration of both HepA and HepB vaccines was evaluated in a controlled clinical trial of 165 subjects, aged 18 to 35 years, who were randomized to receive either HepA vaccine, HepB vaccine, or both vaccines. The formalin-inactivated HepA vaccine ( HAVRIX ) at a dose of 720 EL.U. per mL and the commercially available HepB vaccine ( Engerix-B ) in a dose of 20 mcg/mL were administered at a zero and one month primary vaccination course, followed by a booster at month six . All the vaccines were well-tolerated and highly immunogenic , indicating that synchronous vaccination against both HAV and HBV infection is possible. Studies in infants and children ≤18 suggest that the HepA vaccine does not affect immunogenicity or reactogenicity to diphtheria-tetanus-acellular pertussis, Haemophilus influenzae type b, hepatitis B, MMR , oral poliovirus, or inactivated poliovirus vaccine MMR vaccine A/E The MMR vaccine is generally safe with few serious adverse events reported other than local pain and induration at the site of vaccination. Thrombocytopenic purpura  — Thrombocytopenic purpura has occasionally been observed within two months after receipt of MMR vaccine [32,36-39]. The reported incidence of this complication has varied from one in 30,000 vaccinees in prospective trials [15,36] to one case per 100,000 vaccine doses by passive surveillance [15,37]. Complete recovery from thrombocytopenic purpura has generally been the rule, but some patients develop acute hemorrhagic complications . Individuals who experience an episode of thrombocytopenia after an initial dose of MMR are at greater risk for recurrent thrombocytopenic purpura after rechallenge with this vaccine [39]. Aseptic meningitis  — Aseptic meningitis has been reported in a number of studies evaluating adverse events following MMR vaccination [40-45]. The bulk of cases have presented with typical clinical signs and symptoms of meningeal irritation, and the CSF profile has generally shown a lymphocytic pleocytosis ; recovery has been the rule. Several studies suggest that the risk of aseptic meningitis may be higher in patients vaccinated with the Urabe strain compared with the Jeryl Lynn strain [42-44]: A retrospective survey of aseptic meningitis associated with MMR vaccine was conducted in 13 districts in England and Wales, where 27 cases were identified [40]. All were recipients of vaccines containing the Urabe mumps strain; no cases related to the Jeryl Lynn vaccine were found. The risk of aseptic meningitis post-MMR vaccination was estimated to be one in 11,000 vaccine doses, much higher than that reported in the United States, where the Jeryl Lynn strain is used [41]. Other neurologic complications, including Guillain-Barré syndrome [46] and cerebellar ataxia [47], have rarely been reported following MMR vaccination. Seizures  — MMR vaccination has been previously associated with febrile seizures occurring 8 to 14 days after receipt of vaccine . Approximately one additional febrile seizure occurs among every 3000 to 4000 children vaccinated with MMR vaccine, compared with children who were not vaccinated LONG–TERM COMPLICATIONS  —  Mumps vaccine  has been evaluated as a causal factor in the development of diabetes mellitus and autism , although a definitive link has not been established for either entity. Either the deltoid or gluteal muscle may be used. In children younger than 24 months of age, Ig can be given in the anterolateral thigh muscle Ig can be given concomitantly with the HAV vaccine. Although the antibody titer will be lower than if the vaccine were administered alone, the response is still protective. However, Ig can interfere with the response of other vaccines and should be delayed.
  • Viral hepatitis

    1. 1. Viral HepatitisMohammed AdemB.pharm, M.clinpharmLecturer and clinical pharmacist05/01/13 Mohammed Adem 1
    2. 2. Liver disease: syndromic approach1. Hepatocellular: injury, inflammation, and necrosis of livercells/liver parenchyma2. Cholestatic: inhibition of bile flow3. A mixed pattern : features of both hepatocellular and cholestaticdisease• The pattern of onset and prominence of symptoms can rapidly suggest adiagnosis• Laboratory pattern is characteristic05/01/13 Mohammed Adem 2
    3. 3. Hepatitis• Inflammation of liver parenchyma or hepatocytes:• The are two types : duration based– Acute hepatitis: duration for < 6 months– Chronic hepatitis: lasting for ≥ 6 months05/01/13 Mohammed Adem 3
    4. 4. Acute hepatitis: causesAcute Hepatitis< 6 monthsViral HepatitisA, B/D, C, EEBVCMV …DrugsAcetaminophenIsoniazidAlcohol …ToxinsMushroomscarbon tetrachlorideVascularHypotensionBudd-ChiariAutoimmuneHepatitisMetabolicWilsons Disease05/01/13 Mohammed Adem 4
    5. 5. Chronic hepatitis: causesChronic Hepatitis> = 6 monthsViral HepatitisB/D, CDrugsMTXINHAmiodaronealcohol NAFLDAutoimmuneHepatitisPBCPSCA1ATHHCWilsons05/01/13 Mohammed Adem 5
    6. 6. Acute viral Hepatitis• a systemic infection affecting predominantly the liver• almost all cases are caused by of the five hepatitis viral agents:HAV, HBV/HDV, HCV, HEV• all of these human Heptitis viruses are RNA viruses except HBV• HDV is a defective RNA virus05/01/13 Mohammed Adem 6
    7. 7. Acute viral Hepatitis…o Although these agents can be distinguished by their molecularand antigenic properties  all of them produce clinicallysimilar illnesses.These range from• asymptomatic and inapparent to fulminant and fatal acuteinfections common to all types, and• from subclinical persistent infections to rapidly progressivechronic liver disease with cirrhosis and even HCC , common tothe blood borne types (HBV, HCV, and HDV)05/01/13 Mohammed Adem 7
    8. 8. Acute viral Hepatitis…• Although the rates of acute infection have declined, viral hepatitis remainsa major cause of morbidity and mortality with a significant impact onhealthcare costs.• Significant therapeutic advances have occurred with hepatitis B with theapproval of new agents and updated guidelines for care.• For hepatitis C, the challenge remains of increasing successful outcomeswhile minimizing side effects of therapy05/01/13 Mohammed Adem 8
    9. 9. Acute viral Hepatitis…• Incubation period & risk factors vary with each hepatitis virus• may mimic other systemic infections• most symptoms are non-specific• most patients are asymptomatic05/01/13 Mohammed Adem 9
    10. 10. Incubation Period• Hepatitis A: 15-45 days (30)• Hepatitis B: 30-180 days (70)• Hepatitis C: 15-160 days (50)• Hepatitis D: 21-140 days (35)• Hepatitis E: 15-65 days (40)• Hepatitis G: (14- ? days)05/01/13 Mohammed Adem 10
    11. 11. Acute viral hepatitis: clinical features• Prodromal Sx of acute viral hepatitis are systemic and variable• Constitutional Sx may precede the onset of jaundice by 1–2weeks.– Anorexia, nausea, vomiting, fatigue, malaise, arthralgia, myalgia, headache,photophobia, cough and coryza– Low-grade fever• Sx and signs related to liver dysfunction– Dark urine, clay-colored– By the time of jaundice appears, these will go away or diminish– Enlarged and tender liver– Splenomegaly– Cervical lymphadenopathy05/01/13 Mohammed Adem 11
    12. 12. Mini-case 1• Eden and Bruk, Ethiopian couples returned from theirhoneymoon trip to Central America and developsnonspecific abdominal symptoms followed by clinicaljaundice.• They stayed at a resort, and ate fresh fruits and salads.Serology for hepatitis virus spread by the fecaloral routeis positive. One of the following is the most likely:• hepatitis A virus;• hepatitis B virus• hepatitis E virus• A and C• hepatitis C virus• hepatitis D virus05/01/13 Mohammed Adem 12
    13. 13. Mini-case 2E.T., a 34-year-old medical sales representative, presents to the ED at Black LionHospital with acute onset of jaundice and “dark urine.” He was in good healthuntil 2 weeks ago, when he noted feeling fatigued and weak, which he attributedto his demanding work schedule.He also recalled having a mild headache, loss of appetite, muscle pain, diarrhea,and low-grade fevers from 99°F to 101°F.He attributed these symptoms to the flu and took acetaminophen with plenty offluids. His symptoms persisted until yesterday, when they seemed to resolveunexplainably. He then noted his urine was cola-colored.This morning, he noted jaundice of his eyes and skin and sought medical attention.Mohammed Adem13
    14. 14. MH:a recent respiratory tract infection, treated successfully with levofloxacin.SH:is significant for frequenting the local bar, where he regularly ingests raw meats. Hedenies smoking and recent travel to heptitis A endemic areas, but admits tooccasional alcohol consumption.E.T. has no Hx of sexual exposure, needle use, or transfusions. His currentmedications include oral (PO) diazepam 5 mg at bedtime (HS) as needed (PRN)for “muscle spasms,” but he has not taken diazepam for “several months.” Healso has a seizure disorder sustained after a motorcycle accident 2 years beforeadmission, for which he takes phenytoin 400 mg PO HS.Mohammed Adem14
    15. 15. PE ;significant for a well-developed, well-nourished man in no acute distress. He isalert and oriented, with a temperature of 99°F. His sclerae and skin are icteric,and his abdomen is positive for a tender, enlarged liver, and right upperquadrant (RUQ) pain.Laboratory tests: reveal the following values:Hgb, 16 g/dL (12.3–16.3); Hct, 44% (37.4%–47.0%); WBC, 5,500cells/mm3(3.28–9.29 × 103); AST, 120 U/L (5–40); ALT, 240 U/L (5–40);AP, 86 U/L ( 21–91); total Bl , 3.2 mg/dL (0.2–1.0); Bl (D), 1.5 mg/dL (0–0.2); and phenytoin concentration, 12 mg/L (10–20).The albumin, PT, blood glucose, and electrolytes all are within normal limits.E.T. is negative for anti-HCV, HBeAg, HBsAg, and hepatitis B core antibody(anti-HBc), but is positive for IgM anti-HAV.What clinical features and serologic markers are consistent with viral hepatitis inE.T.?05/01/13 Mohammed Adem15
    16. 16. HEPATITIS A : HAV05/01/13 Mohammed Adem 16
    17. 17. HAV…• HAVis often a self-limiting and acute viral infection of the liverposing a health risk worldwide.•• The infection is rarely fatal.• Although vaccine preventable, HAV continues to be one of themost commonly reported infections.05/01/13 Mohammed Adem17
    18. 18. Epidemiology• Faeco-oral route– where hygiene is poor, infection is almost universal during childhood– As hygiene improves, rate of childhood infection decreases common• Close personal contact– Household, child-care centers– Identifiable risk  sexual (Promiscuous MSM); household contact with person with HAV; IDUs• Contaminated food, water– Infected food handlers, international travelers (endemic areas), immigration• Blood exposure (rare)– 45-50% have no identified source• Despite being detectable in saliva, there are no data to suggest transmissionthrough this mode of contact.NB: It almost always manifests with a self-limited clinical course05/01/13 Mohammed Adem18
    19. 19. Etiology• HAV is a RNA virus. genus Hepatovirus , Picornaviridae family.• Humans are the only known reservoir for the virus andtransmission occurs primarily through the fecal–oral route.• The virus is stable in the environment for at least a month.requires heating foods to a minimum of 85°C (185°F) for 1 minute ordisinfecting with a 1:100 dilution of sodium hypochlorite (bleach) in tap waterfor inactivation.• Multiple genotypes of the virus exist and although the clinicalimplications of infection by particular type are unknown.types I and III are the most commonly identified in human outbreaks05/01/13 Mohammed Adem19
    20. 20. Pathophysiology• HAV infection is usually acute, self-limiting, confers lifelongimmunity.• HAVs life cycle in the human host classically begins withingestion of the virus.• Absorption in the stomach or small intestine allows entry into thecirculation and uptake by the liver.• Replication of the virus occurs within hepatocytes & GI epithelialcells.• New virus particles are released into the blood & secreted into bileby the liver.• The virus is then either reabsorbed to continue its cycle orexcreted in the stool.05/01/13 Mohammed Adem20
    21. 21. Pathophysiology…• The enterohepatic cycle will continue until interrupted by antibodyneutralization.• The exact mechanism of replication & secretion is unknown. however, theinitial viral expansion does not seem to be associated with hepatic injury as peak viral fecal excretion precedes clinical signsand symptoms of infection.• On biopsy, acute hepatitis is marked by hepatocellular degeneration,inflammatory infiltrate, and hepatocyte regeneration.• Hepatocellular degeneration occurs as a result of immune-mediated injuryand not as a direct cytopathic effect of the virus.• Cytolytic T cells mediate hepatocyte lysis to eradicate the virus andmark the cellular immune response with rising hepatic enzyme levels.05/01/13 Mohammed Adem21
    22. 22. Risk Factors• Ingestion of contaminated food substances– Large outbreaks as well as sporadic cases have been traced tocontaminated: Food , Water, Milk• Family member who is affected• Poor personal hygiene• Institutional resident who is affected• Child care centers• Neonatal intensive care units• MSM, IVDU05/01/13 Mohammed Adem 22
    23. 23. Clinical presentations…Mohammed Adem23
    24. 24. Clinical presentations…Signs and symptoms• Symptoms and severity of HAV vary according to age• Children <6 years of age typically are asymptomatic.• The preicteric phase brings nonspecific influenza-like Sx: anorexia,nausea, fatigue, and malaise• Abrupt onset of anorexia, N, V, fever, headache & RUQabdominal pain• Icteric hepatitis is generally accompanied by dark urine, acholic (light-colored)stools, and worsening of systemic Sx.• Pruritus is often a major complaint of icteric patientsMohammed Adem24
    25. 25. Clinical presentations• Incubation period : 15–45 days ; Mean: ~4 weeks• Viremia occurs within 1-2 weeks of exposure as patients begin toshed the virus. viral shedding in feces,• Peak fecal shedding of the virus precedes the onset of clinical Sx& elevated liver enzymes.• Acute hepatitis follows, beginning with the preicteric orprodromal period.The phase is marked by an abrupt onset of nonspecificsymptoms, some very mildMohammed Adem25
    26. 26. Clinical presentations…• unusual Sx : chills, myalgia, arthralgia, cough, constipation, diarrhea, pruritus,and urticaria. Non-specific• Liver enzyme levels rise within the first wks of infection, peaking~ in the 4thwk and normalizing by the 8thwk.• Conjugated bilirubinemia, or dark urine, precedes the onset ofthe icteric period.Mohammed Adem26
    27. 27. Clinical presentations…• The concentration of virus declines at this point andpatients are generally considered noninfectious~ 1 week after the onset of jaundice.• GI Sx may persist or subside during this time and somepatients may have hepatomegaly.• Duration of the icteric period varies and corresponds todisease duration. It averages between 7 and 30 days.Mohammed Adem27
    28. 28. Clinical presentations…Physical examination• Icteric sclera, skin, and secretions• Mild weight loss of 2–5 kg• HepatomegalyMohammed Adem28
    29. 29. Clinical presentations…Laboratory findings• Positive-serum IGM ,• IgG replaces IgM and indicates host immunity following the acute phase.• Mild elevations of serum bilirubin, -globulin, and ALT , AST values to about 2Xnormal in acute anicteric disease• Elevations of AP, - GGT and total bilirubin in patients with cholestatic illness• Serum HAV becomes detectable 5 - 10 days before the onset of symptomsand can persist for monthsMohammed Adem29
    30. 30. Prognosis• HAV does not lead to chronic infections.• Some pts may experience Sx for up to 9 months.• Virtually all previously healthy patients with hepatitis A recovercompletely from their illness, with no clinical sequelae.• Complete clinical and biochemical recovery is to be expected in 1–2months.• No chronic carrier state• fatality rate: ~ 0.1%Mohammed Adem30
    31. 31. Complications• Rarely, patients experience complications from HAV, includingrelapsing hepatitis, cholestatic hepatitis, and fulminant hepatitis• Relapsing hepatitis :– Recurrence of symptoms– Elevated liver enzyme levels– Jaundice (occasionally)– Fecal excretion of HAV– Even when this occurs, hepatitis A remains self-limited and does not progress to chronic liverdisease.• Cholestatic hepatitis– Characterized by protracted cholestatic jaundice and pruritus• Fulminant hepatitis (massive hepatic necrosis): Rare 0.1% yet high fatality– Primarily in older adults (50), younger children and in persons with underlying chronic liver disease05/01/13 Mohammed Adem31
    32. 32. Diagnosis• History: particular attention to risk factors• Clinical Criteria:acute onset of fatigue, abdominal pain, loss ofappetite, intermittent nausea and vomiting, jaundice• Laboratory:serum aminotransferases, and serologic testing for anti-HAV antibodies.IgM anti-HAV is the diagnostic test of choice• Appears very soon after infection• Disappears 3–6 months later• Incidental presence of rheumatoid factor can yield false-positive results• IgG anti-HAV appears later in the acute phase but persists for decades05/01/13 Mohammed Adem 32
    33. 33. Differential diagnosis1. Other hepatitis viruses2. Other viral illnesses frequently affect the liver– Infectious mononucleosis , Cytomegalovirus , Herpes simplex1. Many drugs and certain anesthetic agents2. Alcoholic hepatitis3. Acute Cholecystitis4. Disorders in pregnancy that may be confused with viralhepatitis• Acute fatty liver of pregnancy , Cholestasis of pregnancy , Eclampsia ,1. Many, many more…05/01/13 Mohammed Adem33
    34. 34. Treatment• Mainstay of therapy is supportive care.• Specific treatment is not necessary.– Most patients hospitalized with hepatitis A excrete little if any HAV– Likelihood of HAV transmission from these patients during theirhospitalization is low.Nonetheless, universal precautions are recommended.Mohammed Adem34
    35. 35. TreatmentDesired Outcome• The ultimate goal of therapy is complete clinical resolution.• Other goals: reducing complications, normalization of liver function,and reducing infectivity and transmission.• The majority of pts are expected to fully recover without clinicalsequelae.• clinical resolution within 6 months of the infection, & a majoritywill have done so by 2 months.• Rarely, Sx persist for longer or patients relapse.Mohammed Adem35
    36. 36. Treatment…General Approach• In pts who develop liver failure, transplant is the only option.• Prevention and prophylaxis are key to managing the virus.• Immunoglobulin: for pre- and postexposure prophylaxis offers passive immunity.• Active immunity is achieved through vaccination.Children and at-risk adults  to reduce the overall incidenceMohammed Adem36
    37. 37. Treatment…• Most patients hospitalized with hepatitis A excrete little if anyHAV. Likelihood of transmission is low• Prevaccination serologic testing to determine susceptibility isgenerally not recommendedif the cost of the test is less than that of the vaccine andif the person is from a moderate to high endemic area and likely to have priorimmunity• Prevaccination serologic testing of children is not recommended.• postvaccine serologic testing is not recommended.Due to high vaccine responseMohammed Adem37
    38. 38. Prevention• HAV is easily preventable with vaccination.• vaccine programs have targeted children as the most effectivemeans to control HAV.• vaccination programs among children from high-incidence states >70% reduction in the annual incidence of new HAV infections• Two vaccines for HAV are available and are incorporated into theroutine childhood vaccination schedule.05/01/13 Mohammed Adem38
    39. 39. Prevention… Recommendation for HAV Vaccine05/01/13 Mohammed Adem39
    40. 40. Prevention…• Routine prevention of HAV transmission includeswith soap and water after using the bathroom,Regular hand washing changing a diaper, and before food preparation.• For travelers to countries with high endemic rates of HAV, evenshort-term stays in urban and upscale resorts are not risk free.contaminated waterfresh produce, and any uncooked foods pose a risk05/01/13 Mohammed Adem40
    41. 41. Vaccines• Havrix and Vaqta: are available for pediatric and adult use. USAthe two inactivated virus vaccines. 1995• The differences in the two vaccines are in the use of apreservative and in expression of antigen content.• Vaqta: formulated without a preservative anduses units of HAV antigen to express potency.• Havrix: uses 2-phenoxyphenol as a preservative andantigen content is expressed as enzyme-linked immunosorbent assayunits.• Pediatric dosing is indicated for children 1 to 18 years of age, andadult dosing is for patients ages 19 years and older05/01/13 Mohammed Adem41
    42. 42. Vaccines …• Although high seroconversion rates of 94% are achieved with thefirst dose, both vaccines recommend a booster shot to achieve thehighest possible antibody titers.• In situations of postexposure prophylaxis, previously onlyimmunoglobulin was indicated but recent guidelines changesallow the use of vaccines for this indication.The change to the use of the vaccine is advantageous asvaccination confers the benefit of long-term immunity against HAV.• Both vaccines may be given concomitantly with immunoglobulinand the two brands are interchangeable for booster shots.05/01/13 Mohammed Adem42
    43. 43. Recommended dosing of the Vaccines05/01/13 Mohammed Adem43
    44. 44. Vaccines … monitoring issues• Response to the vaccine as determined by detection of anti-HAVafter vaccination.• Vaccine efficacy may be reduced in certain pt groups.eg. In HIV infected pts, greater immunogenic response may correlate with higher baseline CD4 counts.females and patients with CD4 counts >200 high response rate• most common S/E: soreness & warmth at the injection site, headache, malaise, pain• Reported serious A/E: causality not yet establishedanaphylaxis, Guillain-Barré syndrome, transverse myelitisReported brachial plexus neuropathy, multiple sclerosis,encephalopathy, and erythema multiforme.Note: the incidence of these events was similar in the general population. Vacc vs unvaccThe vaccine is considered safe05/01/13 Mohammed Adem44
    45. 45. Vaccines … Twinrix• Twinrix is a bivalent vaccine for HAV and HBV. in 2001• It is approved for people ages 18 and older and is given at 0, 1,and 6 months.• Although seroconversion exceeds 90% for HAV after the firstdose , the full three-dose series is required for maximal HBV seroconversion.• The combined vaccine offers the advantage of immunizationagainst both types of hepatitis in a single vaccine.05/01/13 Mohammed Adem45
    46. 46. Immunoglobulin/Ig• Used in persons for whom vaccination is not an option.pre- or postexposure prophylaxis• provides protection by passive transfer of antibody• is preferred forchildren <12 months of age andpostexposure prophylaxis in patients aged >40 years, pts with chronic liver disease,and persons allergic to any part of the vaccine.• most effective if given in the incubation period of the infection. Receipt of Ig within the first 2 weeks of infection will reduce infectivity and moderate theinfection in 85% of patients.Note: Patients who receive at least 1 dose of the vaccine at least 1 month earlierdo not need pre- or postexposure prophylaxis with Ig.05/01/13 Mohammed Adem46
    47. 47. Ig…• International travelers are the major patient population receivingpreexposure prophylaxis with Ig.• vaccination or prophylaxis with Ig is recommended for travelers tocountries with high endemic rates of HAV. A/E like anphylaxis IgA deficiency• Patients who had an anaphylaxis reaction to Ig should not receiveit. There is no C/I for use in pregnancy or lactation.• Dosing of Ig is the same for adults and children.• a single dose of 0.02 mL/kg IM: For postexposure prophylaxis and for short-term preexposure coverage of <3 months,05/01/13 Mohammed Adem47
    48. 48. Ig…• For long-term preexposure prophylaxis of 5 monthsa single dose of 0.06 mL/kg is used.• People recently exposed to HAV and not been previouslyvaccinated  Ig is indicated fora) close personal contact with an HAV-infected person;b) all staff and attendees of daycare centers when HAV is documented;c) common source of exposure (food handler)d) classroom contacts of an index case patient; ande) schools, hospitals, and work settings where close personal contact occurred with thecase patient• Ig can be given concomitantly with the HAV vaccine. the response isprotective05/01/13 Mohammed Adem48
    49. 49. Ig…• The MMR (measles, mumps, and rubella) vaccine should be delayed for a minimum of3 months after receipt of Ig.• The varicella vaccine must be delayed for 5 months.• Ig should not be given to patients who received the MMR within 2 weeks or thevaricella vaccine within 3 weeks.• In situations where the benefits of Ig outweigh the benefits of the othervaccines, revaccination can be performed after Ig administration.• For the MMR, revaccination should be at least 3 months later, and for thevaricella vaccine, at least 5 months later.• Ig does not interfere with inactivated vaccines and may be administered safely withother vaccines traditionally given to travelers to some developing countries, such as theoral poliovirus or yellow fever vaccine.05/01/13 Mohammed Adem49
    50. 50. Pharmacoeconomic Considerations• The costs of an HAV outbreak are significant, yet routine vaccination of allindividuals is not cost-effective. So,• targeting at-risk populations, the majority of cases can be prevented.Children play a pivotal role in disease persistence• Using vaccine is cost-effective in children and offers the most benefit to thepersonal contacts of children.• The use of the combined HAV-HBV vaccine is effective in reducing costsassociated with HAV among persons who are at increased risk for infection.05/01/13 Mohammed Adem50
    51. 51. References• Harrison’s principle of internal medicine 18thed• Joseph T dipro; Pharmacotherapy apathophysiologic approach 8thed• Applied therapeutics the clinical use of drugs 9thed05/01/13 Mohammed Adem 51

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