Petrol hbv siham

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  • hepatotropic members of the hepadnavirus (HBV) and flavivirus (HCV) families
  • It has been difficult to elucidate the viral and host factors at play in these infections, however, largely because the host range of HBV and HCV is limited to humans and chimpanzees (3, 19) and because cell culture systems and small animal
  • , and the outcomes for humans and chimpanzees are similar
  • is a life long, dynamic disease Fibrosis can be reversibleDrugs can decrease fibrosis progression
    HBV is a life long can be controlled but not cured
  • Case presentation significant past medical history 1
  • 2
  • 3
  • Genotypes May Have Related Clinical Implications
    Molecular variation and change in the hepatitis B virus (HBV) genome over time have resulted in the emergence of at least eight genotypes.1,2 HBV genotypes A to H are classified based on an intergroup divergence of 8% or more in nucleotide sequence over the entire genome.3-6 In recent years, substantial progress has been made toward understanding the epidemiology and virologic significance of the eight different HBV genotypes. While the clinical and therapeutic relevance of HBV genotypes continues to be investigated and debated, accumulating evidence suggests that HBV genotypes may indeed affect the natural history of liver disease and potentially have a role in the management of patients with chronic hepatitis B.
    The various genotypes differ in their geographic distributions and long-term clinical implications7,8 . Genotype A appears to be associated with higher rates of sustained treatment response and HBsAg clearance. Compared with genotype C, genotype B is associated with the earlier appearance of antibodies against HBeAg and slower progression, whereas genotype C causes more severe disease and is particularly likely to be associated with HCC.7 The risk of anti-e-positive chronic hepatitis B and cirrhosis is generally higher in genotype D than in genotype A.8 Despite these hints of clinical relevance, the implications of a particular genotype for treatment outcome and patient prognosis are not entirely clear; therefore, genotyping is not routine in clinical practice.7
    The eight HBV genotypes show a distinct geographic distribution.1,2,7,8
    Genotype A is most frequently detected in northern Europe, North America, India, and sub-Saharan Africa. Genotypes B and C are prevalent in East Asia and the Pacific. Genotype D is most often found in southern and central Europe, the Middle East, and parts of central Asia, North America, India, and Africa. Genotype E has been detected in Africa. Genotypes F and H have been detected in Central and South America. Genotype G has been identified in France, Germany, Mexico, and the United States. However, the geographic distribution of HBV genotypes is not static and may vary over time and with population migration.9
    Sablon E, Shapiro F. Hepatitis B and C genotyping: methodologies and implications for patient management. J Gastroenterol Hepatol. 2004;19:S329-S337.
    Schaefer S. Hepatitis B virus: signifi cance of genotypes. J Viral Hepat. 2005;12:111-124.
    Norder H, Courouce AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology. 1994;198:489-503.
    Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol. 2000;81(pt 1):67-74.
    Arauz-Ruiz P, Norder H, Robertson BH, et al. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol. 2002;83(pt 8):2059-2073.
    Bartholomeusz A, Schaefer S. Hepatitis B virus genotypes: comparison of genotyping methods. Rev Med Virol. 2004;14:3-16.
    Wai CT, Fontana RJ. Clinical significance of hepatitis B virus genotypes, variants, and mutants. Clin Liver Dis. 2004;8(2):321-352.
    Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? Hepatology. 2004;40(4):790-792.
    Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS Jr, Luketic VA, Terrault N, Lok AS. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125(2):444-451.
  • 3
  • DNA/ ALT
  • *1 IU = 5.6 copies; #Normal ALT for men = 30 U/ml and for women = 19 U/ml
    Keeffe EB, et al. Clin Gastroenterol Hepatol.2006.
  • (IU/ml
  • more effective than lamivudine
  • Entecavir (Baraclude)/ Lamivudine (Zeffix) Nucleoside
    Tenofovir (Viread) adefovir (Hepsera) Nucleotide
  • She has now been on lamivudine continuously for more than 1 year.
  • Risk of developing HCC by baseline HBV DNA and HBsAg levels in ERADICATE-B cohort (2688 HBV carriers)
    In HBV carriers with low viral load (< 2000), patients with HBsAg > 1000 had a 5-fold increase of HCC risk than those with HBsAg < 1000.
  • The recent update of REVAEA-HBV study reported in AASLD last yr also showed a similar finding.
  • Lamivudine was then stopped
  • Di Marco V for AISF Lamiudine Study Group, Hepatology. 2004; 40: 883-91
  • Primary aim: prolonged viral suppression
  • Primary aim: prolonged viral suppression
  • ????
  • Petrol hbv siham

    1. 1. Hepatitis B & C A quick update Prof Siham Abdelrehim Faculty Of Medicine / Alexanderia Univ sihamrehim@yahoo.com
    2. 2. Impact of Hepatitis Hepatitis can be caused by: Harmful consumption of alcohol Some chemicals and drugs Viruses – 5 known A, B, C, D & E Inflammation of the liver – natural response to injury Scar tissue = Fibrosis Extensive scarring = Cirrhosis HBV & HCV require long term monitoring
    3. 3. One in 12 people worldwide are living with chronic hepatitis B or C World Hepatitis Alliance Chronic hepatitis B & C are responsible for over 80% of the worlds liver cancer (HCC) ASHM/NSWCC 2008
    4. 4. Hepatitis B and Hepatitis C: Stealth and Cunning The hepatitis B virus (HBV) and hepatitis C virus (HCV) are: • noncytopathic • hepatotropic • cause acute and chronic necroinflammatory liver disease and hepatocellular carcinoma (HCC)
    5. 5. Hepatitis B and Hepatitis C: Stealth and Cunning • • The two viruses could represent very different antigenic challenges to the immune response, and this could have an important impact on the outcome of the infection. Once infection is established, differences in HBV and HCV antigenic burden could also have an impact on viral clearance. In particular, it has been shown by the use of highly sensitive and specific immunohistochemical reagents that HBV can infect up to 100% of the hepatocytes
    6. 6. Hepatitis B and Hepatitis C • It is widely believed that the outcome of both infections and the pathogenesis of the associated liver diseases are determined by host-virus interactions mediated by the immune response.
    7. 7. Hepatitis B and Hepatitis C • • HBV is a stealth virus that establishes itself very efficiently without alerting the innate immune system to its presence, although it is readily controlled when the adaptive immune response is induced. In contrast, HCV strongly induces yet cunningly evades the innate immune response and also defeats the adaptive immune response by mutation and functional inactivation
    8. 8. Hepatitis B and Hepatitis C • Although host factors contribute importantly to the outcome of HBV and HCV infection, viral factors are also critically involved. Perhaps the strongest evidence that viral factors play a role in the outcome of HBV and HCV infection is that more than 95% of adult-onset HBV infections are self limited, while more than 70% of adult-onset HCV infections persist.
    9. 9. HBV • HBV is a dynamic disease ,changes over time • Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults • Reactivation can occur even in those who have lost HBsAg
    10. 10. Case presentation 20 year old student with no significant past medical history is referred for evaluation of HBsAg positivity She is fit and healthy and asymptomatic She denies a history of blood transfusion or intravenous-drug use. Her mother was diagnosed with hepatitis B and end stage of liver disease 8 months ago.
    11. 11. Case presentation On Examination No stigmata of CLD Abdomen: soft, non-distended, non-tender, liver edge smooth, liver span 8 cm by percussion, no splenomegaly Blood HBsAg: positive Hepatitis C virus (HCV) antibody (Ab): negative
    12. 12. Which of the following blood tests would provide the most useful information to characterize the status of chronic hepatitis B and guide recommendations regarding antiviral therapy? A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb) B) HBeAg, HBeAb, and HBV genotype C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level D) HBeAg, HBeAb, and HBV DNA viral load
    13. 13. Which of the following blood tests would provide the most useful information to characterize the status of chronic hepatitis B and guide recommendations regarding antiviral therapy? A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb) B) HBeAg, HBeAb, and HBV genotype C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level D) HBeAg, HBeAb, and HBV DNA viral load
    14. 14. The Emerging Role of HBV Genotypes There are 8 genotypes of hepatitis B (A through H) Although it is not routine, it may assume a role in the management of hepatitis B Clear association with: Precore/core promoter mutations Rates of HBeAg clearance Development of HBeAg-neg Chronic Hepatitis B
    15. 15. HBV Genotypes May Have Clinical Implications F D B – Earlier appearance of HBeAg antibodies and slower progression (vs C) A,B,C, A – Higher rates of sustained treatment response A,G D,G Anti-e-positive chronic hepatitis B and cirrhosis Dhigher than in A D C D D E D Ba F F H Bj C A A,B,C,D C – Liver disease more severe than in B, associated with HCC Adapted from Fung SK et al. Hepatology. 2004;40:790-792. Copyright © 2004, American Association for the Study of Liver Disease. Reproduced with permission of John Wiley & Sons, Inc.
    16. 16. Back to the case Which of the following blood tests would provide the most useful information to characterize the status of chronic hepatitis B and guide recommendations regarding antiviral therapy? A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb) B) HBeAg, HBeAb, and HBV genotype C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level D) HBeAg, HBeAb, and HBV DNA viral load
    17. 17. Case presentation Further Blood results AST ↑ 95 U/L ALT ↑ 132 U/L ALP N 121 mg/d Bilirubin N HBeAg: negative HBeAb: positive HBV DNA: 400,000 IU/mL
    18. 18. What is the significance of HBeAg -ve CHB? • Clinically silent for years • Severe necroinflammation in >50%, cirrhosis in 25-40% • Rare spontaneous sustained remission • Fluctuations in viraemia and ALT • HBV DNA may be persistently < 105 copies/mL but yet has significant liver disease
    19. 19. Which statement is false regarding this patient's hepatitis B status? 1.She is an inactive carrier of hepatitis B 2.She is not in the immune-tolerant phase 3. She likely has a mutation in the precore or core promoter region of the HBV genome 4.HBeAg positivity is associated with a better prognosis than HBeAg negativity
    20. 20. Which statement is false regarding this patient's hepatitis B status? 1.She is an inactive carrier of hepatitis B 2.She is not in the immune-tolerant phase 3. She likely has a mutation in the precore or core promoter region of the HBV genome 4.HBeAg positivity is associated with a better prognosis than HBeAg negativity
    21. 21. Which statement is false regarding this patient's hepatitis B status? HBeAg Anti-HBe HBV-DNA ALT immune tolerance immune clearance inactive carrier reactivation
    22. 22. NIH Definition of Inactive HBsAg Carrier • Presence of HBsAg and anti-HBe in serum • Serum HBV DNA < 105 copies/ml • Persistently normal serum ALT > 6 months • Liver histology (not essential) HAI grade < 3
    23. 23. Patient's hepatitis B status HBeAg Anti-HBe DNA HBV-DNA ALT immune tolerance Treat immune clearance inactive carrier reactivation Treat Who should be considered for treatment?
    24. 24. What level of HBV DNA would you start treatment? a. HBV DNA ≥ log 10 4 b. HBV DNA ≥ log 10 5 c. Any level of HBV DNA
    25. 25. HBV Treatment Guidelines HBeAg + + + – – – HBV DNA (IU/ml)* ALT Management < 20,000 Normal# Follow, no treatment ≥ 20,000 Normal Consider biopsy; treat if diseased ≥ 20,000 Elevated Treat < 2,000 Normal Follow, no treatment ≥ 2,000 Normal Consider biopsy; treat if diseased ≥ 2,000 Elevated Treat *1 IU = 5.6 copies; # Normal ALT for men = 30 U/ml and for women = 19 U/ml Keeffe EB, et al. Clin Gastroenterol Hepatol.2006.
    26. 26. What level of HBV DNA would you start treatment? a. HBV DNA ≥ log 10 4 b. HBV DNA ≥ log 10 5 c. Any level of HBV DNA + ALT elevated ≥ 2,000 c/ml IU = 5.6 copies
    27. 27. Evolution of Chronic HBV Therapy Over Time Peginterferon alfa-2a Entecavir Lamivudine 1990 Interferon alfa-2b 1998 2002 Adefovir 2005 Tenofovir 2006 Telbivudine 2008
    28. 28. Treatment Nucleoside Analogues -- Lamivudine, Entecavir • Lamivudine • Dose : 100 mg PO q daily • Good for reducing the risk of progression to hepatic decompensation in patients with cirrhosis or advanced fibrosis • Pregnancy category B--Not teratogenic in animal studies and successful use with pregnant women • Problem: High rates of resistant mutations • Side effect: lactic acidosis • Entecavir – 1st line • 0.5 to 1mg PO • very effective; low resistance and greater than 90% HBV DNA clearance rate in HBeAg positive pts • Side effect: lactic acidosis
    29. 29. Treatment cont. Nucleotide analogues • Tenovir • Dose: 300mg qd • Highly effective with low resistance • Well tolerated • Adefovir – 1st line • Dose: 10mg daily • Resistance less than Tenovir • Side effect: nephrotoxicity and lactic acid
    30. 30. NAs: Potency versus resistance More potent than Adefovir Nucleoside analogue Nucleotide analogue TDF ETV LdT LAM ADV Potency of HBV DNA suppression Likelihood of resistance development
    31. 31. HBV life cycle Neutralizing antibodies (HBsAg-specific) Hepatocyte-specific receptor Nuclear steps require liver-specific elements Reverse transcription Essential for virion formation Integration NOT essential (contrast to retroviruses) HBV polymerase inhibitors (Lamivudine, Adefovir, Entecavir,Tenofovir)
    32. 32. Back to the case What is the most appropriate management strategy at this time? A) Start lamivudine 100 mg once daily B) Start adefovir 10 mg once daily C) Start entecavir 0.5 mg once daily D) Start Tenofovir 300 mg E) Observation; follow liver function tests every 3 months for 1 year
    33. 33. What is the most appropriate management strategy at this time? A) Start lamivudine 100 mg once daily B) Start adefovir 10 mg once daily C) Start entecavir 0.5 mg once daily D) Start Tenofovir 300 mg E) Observation; follow liver function tests every 3 months for 1 year
    34. 34. She received lamivudine continuously After 6 ms her laboratory studies were as follows: AST N ALT N HBV DNA -ve
    35. 35. What are your recommendations at this time? A) Continue to follow serum aminotransferases and HBV DNA levels at 6 months intervals B) Continue lamivudine 100 mg once daily for at least 3 years after HBV load is undetectable C) Given that the HBV load is undetectable, her disease is classified as inactive and she no longer needs regular follow-up at all. D) Given that the HBV load is undetectable, she needs regular follow HBsAg level
    36. 36. What are your recommendations at this time? All except A) Continue to follow serum aminotransferases and HBV DNA levels at 6 months intervals B) Continue lamivudine 100 mg once daily for at least 3 years after HBV load is undetectable C) Given that the HBV load is undetectable, her disease is classified as inactive and she no longer needs regular follow-up at all. D) Given that the HBV load is undetectable, she needs regular follow HBsAg level
    37. 37. She has now been on lamivudine continuously for more than 2 years Her most recent laboratory studies were as follows: AST N ALT N HBV DNA -ve HBsAg titre 54320
    38. 38. qHBsAg can predict spontaneous HBsAg loss in HBV carriers Serum HBsAg level <100 IU/ml at 1 year post-HBeAg seroconversion can predict HBsAg loss within 6 years1 HBsAg <10 IU/ml is the strongest predictor of HBsAg loss in HBeAg-negative patients who have HBV DNA <2000 IU/ml2 Decreasing HBsAg level (<200 IU/ml or a decrease of ≥ 1 log 10 IU/ml) can predict HBsAg seroclearance in inactive CHB patients3 1. Tseng, Kao et al. Gastroenterology 2011 2. Tseng, Kao et al. Hepatology 2012 3. Chen YC, et al. Clin Gastroenterol Hepatol 2011
    39. 39. HBsAg level is an important risk factor in patients with low HBV DNA level (<2000 IU/mL) ERADICATE-B (2688 HBV carriers) 5-fold risk increase by univariate analysis Tseng, Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012
    40. 40. HBV DNA, HBsAg and ALT levels during different phases of CHB Janssen et al. Gut 2012.
    41. 41. The case • She was continued on lamivudine. After 36 months HBV DNA below detectable levels. ALT 20 U/l • Well until 6 months later her ALT 90 U/l • Repeat HBV DNA 6,000 IU/ml • What is the cause for her virologic and biochemical breakthrough?
    42. 42. Extended LAM therapy in HBeAg(-) CHB: The Italian experience (616 patients) 100 Virological response 1 89% Virological Breakthrough2 80 % patients 63% 61% 60 37% 40 20 0 48% 52% 39% 11% 1 year 2 years 3 years 4 years Virological Response to LAM (4 Years): Resistance Exceeds Efficacy 1 HBV DNA < 105 copies/mL 2 Re-appearance of HBV DNA > 105 copies/mL
    43. 43. Rise in serum transaminases Worsening of liver disease
    44. 44. Once Viral Resistance has developed Add or Switch? Should we continue or stop the lamivudine? If continue for how long? Besides lamivudine, are there any other options?
    45. 45. What treatment options for lamivudine resistant ? a. switch to adefovir b. lamivudine combines with adefovir c. switch to entecavir d. switch to interferon
    46. 46. Rescue Therapy for AntiviralResistant HBV • • • • Lamivudine-R • Add adefovir/tenofovir • Switch to tenofovir or switch to entecavir (risk of subsequent entecavir-R) Adefovir-R* • Add lamivudine or switch to tenofovir • Switch to entecavir (if no prior LAM-R) Entecavir-R* • Add or switch to adefovir or tenofovir Multidrug R → ???
    47. 47. Back to the patient • • • • Started on tenofovir 300mg /d Seen by me every 6 ms ALT 49 -ve DNA , HBsAg 5000 Any mistakes in treatment? What medication should we use next?
    48. 48. HBV Control Inflammatory: normalize serum ALT. Virologic: decrease HBV DNA. Immune: seroconversion HBeAg to HBeAb HBsAg to HBsAb HBV never “cured” but controlled
    49. 49. Therapeutic endpoints over time Improved histology Anti-HBe+ Loss of HBeAg Loss of HBV DNA TIME Anti-HBs+ Loss of HBsAg
    50. 50. Antiviral Treatment of HBeAg (+) mild-moderate liver disease ALT > 2 ULN and/or histology > F1 Lamivudine/Adefovir/Entecavir/Tenofovir HBeAg seroconversion? No ALT normal? Yes Continue therapy Yes Continue treatment for at least 6 months No Drug resistance ?
    51. 51. Antiviral Treatment of HBeAg (-) mild-moderate liver disease ALT > 2 ULN and/or histology > F1 Lamivudine/Adefovir/Entecavir/Tenofovir ALT normal Yes Continue treatment indefinitely No ALT↑ Drug resistance ?
    52. 52. Treat Today To Prevent Tomorrow
    53. 53. HBV Prevention • Active immunization • Recombinant subunit vaccine produced in yeast (HBsAg) • Combination vaccine with HAV available (Twinrix) • Highly effective • Component of routine childhood vaccine series • Recommended for high risk adults • Health care and long-term care facility workers, HD patients, IVDU, travelers, chronic liver disease • Seroconversion rate declines with age and immunosuppression • • >95% for age < 30 yo, but only 50% for age > 60 yo Passive immunization • Immune globulin available for post-exposure prophylaxis
    54. 54. IgG HBcAb???? A hepatitis panel is ordered for a 27 year old female as part of a routine workup for abdominal pain. Results of serological testing a negative for HBeAg and HBsAg, but positive for IgG HBcAb. The patient has been exposed to Hep B. a. b. c. d. e. Patient has recovered Patient is in acute infective disease state Window period Chronically infected Patient was never infected
    55. 55. THANK YOU
    56. 56. Hepatitis C virus (HCV)    Family: Flaviviridae Enveloped Non-segmented positive (+) strand RNA genome Cambridge University Press
    57. 57. HCV Clinical Manifestations  Transmission – IVDU, sexual (less than HBV), transfusion, transplant – Vertical  Primary symptoms – Acute infection often asymptomatic – Only 20% clear infection (contrast with HBV)  Complications – 70-80% progress to chronic infection – 20% will develop cirrhosis (over 20 years) – HCC risk increased (1-4% per year) – Extrahepatic manifestations – Mixed cryoglobulinemia
    58. 58. HCV Diagnosis and Treatment  Diagnosis – Serologies – Viral genome detection (RT-PCR)  Treatment – Interferon α (frequent adverse reactions) – Ribavirin – Rapid resistance if use alone – Combination therapy most effective (IFN α + Rib) – <50% sustained response – Active area of investigation for new targets/drugs – R7128 and IDX184 - polymerase inhibitors – VX-950 (Telaprevir) - protease inhibitor – Debio-025 – cyclophilin inhibitor – Liver transplantation

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