HBV Treatment & Progression PDF

Hepatitis B During this half century... identifyed the causative agent – hepatitis B virus (HBV) understood its biology and the disease it causes have vaccines that can prevent HBV infection antiviral therapy that can suppress HBV replication and prevent progression o...

Hepatitis B During this half century... identifyed the causative agent – hepatitis B virus (HBV) understood its biology and the disease it causes have vaccines that can prevent HBV infection antiviral therapy that can suppress HBV replication and prevent progression of HBV-related liver disease. 2020 prevalence of HBV infection and morbidity and mortality from Nobel Prize in medicine was awarded to Baruch S. chronic HBV infection has Blumberg in 1976 for the discovery of Australia antigen  The way and the story.. In 1970, 5 years after the discovery of Au Ag, the World Health Organization (WHO) recommended screening of blood donors for HBsAg => marked decline in post-transfusion hepatitis Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Am J Med Sci 1975; 270(2): 329–334. Senior JR, Sutnick AI, Goeser E, London WT, Dahlke MB, Blumberg BS. Reduction of post-transfusion hepatitis by exclusion of Australia antigen from donor blood in an urban public hospital. Am J Med Sci 1974; 267(3): 171–177. Advances in molecular biology techniques in the late 1970s and early 1980s led to a boom in understanding of HBV virology=> HBV is a DNA-containing virus that replicates via reverse Summers J, Mason WS. Replication of the genome of a hepatitis B–like virus transcription by of a pregenomic reverse RNA. transcription of an RNA intermediate. Cell 1982; 29 (2): 403–415. The way and the story.. In 1972, a new antigen associated with HBV – hepatitis B e antigen (HBeAg) – was discovered. It was quickly realized that presence of HBeAg was associated with infectivity and liver injury; several studies in the early 1980s found that some HBeAg- negative patients had high levels of HBV replication and continued hepatic inflammation. Magnius LO, Espmark JA. New specificities in Australia antigen positive sera distinct from the Le Bouvier determinants. J Immunol 1972; 109(5): 1017–1021. The way and the story.. The four major serotypes recognized in the 1980s were :adw, adr, ayw and ayr. With advances in molecular biology, the concept of HBV serotypes has been replaced by HBV genotypes. There are at least 10 HBV genotypes (A–J) which vary in geographical distribution Le Bouvier GL. Editorial: subtypes of hepatitis B antigen: clinical relevance? Ann Intern Med 1973; 79(6): 894–896 The way and the story.. The ccc DNA - has a long half-life in nondividing hepatocytes and is not affected by currently approved nucleos(t)ide analogues !!!!! This explains why : despite rapid suppression of HBV DNA, HBsAg declines slowly during nucleos(t)ide analogue therapy viral relapse occurs in most patients when nucleos(t)ide analogues are stopped. some studies estimated it would take >50 years of continuous nucleos(t)ide analogue therapy to achieve HBsAg clearance. Chevaliez S, Hezode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58(4): 676–683. The story of the treatment.. During the 1960s and 1970s, hepatitis B was often mixed with other chronic hepatitis and treated with corticosteroids. In the late 1970s, the harmful effects of corticosteroids in patients with chronic hepatitis B were recognized and confirmed in a randomized controlled trial. Greenberg HB, Pollard RB, Lutwick LI, Gregory PB, Robinson WS, Merigan TC. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Engl J Med 1976; 295 (10): 517–522. The story of the treatment.. The first antiviral treatment for hepatitis B – standard interferon, was not approved until 1992 although the first clinical trials were conducted in the 1970s. Greenberg HB, Pollard RB, Lutwick LI, Gregory PB, Robinson WS, Merigan TC. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Engl J Med 1976; 295 (10): 517–522. Perrillo RP, Schiff ER, Davis GL et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med 1990; 323(5): 295–301. The story of the treatment.. Lamivudine - 1998 = major step in the development of HBV therapeutics. Lamivudine is administered orally and is well tolerated even in patients with decompensated cirrhosis or recurrent hepatitis B after liver transplantation !!! lamivudine is associated with a high rate of drug resistance and virologic breakthrough can lead to hepatitis flares and in some instances hepatic decompensation and death Ling R, Mutimer D, Ahmed M et al. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology 1996; 24 (3): 711–713. Tipples GA, Ma MM, Fischer KP, Bain VG, Kneteman NM, Tyrrell DL. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 1996; 24(3): The story of the treatment.. pegylated interferon -2005 simplicity in administration – once a week and increased efficacy. has weaker antiviral activity than nucleos(t)ide analogues, but it results in higher rates of HBeAg and HBsAg loss. Lau GK, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAgpositive chronic hepatitis B. N Engl J Med 2005 Marcellin P, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAgnegative chronic hepatitis B. N Engl J Med 2004; Recent studies suggest that interferon may accelerate degradation of cccDNA and/or decrease its transcription thus explaining its greater effect on decreasing HBV proteins. Belloni L, Allweiss L, Guerrieri F et al. IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest 2012; 122(2): 529–537. Lucifora J, Xia Y, Reisinger F et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014; 343(6176): 1221–1228. The story of the treatment.. 2000-2008 - three other nucleos(t)ide analogues telbivudine, entecavir and tenofovir disoproxil fumarate were approved for hepatitis B. The low rates of drug resistance Maintainance of the suppression of HBV replication during long-term treatment Reverse fibrosis as well as cirrhosis Chang TT, Liaw YF, Wu SS et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52(3): 886–893. Marcellin P, Gane E, Buti M et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381(9865): 468–475 The story of the treatment.. Oral antivirals = preferred HBV treatment in most countries Disadvantages : the rates of HBeAg and HBsAg loss are low treatment has to be continued for many years if not for life. much of the current debate about nucleos(t)ide analogue treatment is whether treatment can be stopped. IOM Report: Burden of HBV Disease 15% to 25% risk of early death caused by liver cancer or end-stage liver disease among patients with chronic HBV infection 1. IOM. Hepatitis and liver cancer: a national strategy for prevention and control of Hepatitis B and C. Washington, DC: The National Academies Press; 2010. p 44. 2. Beasley R, et al. In: Hollinger FB, et al, eds. Proceedings of the 1990 international symposium on Viral Hepatitis and Liver Disease: Contemporary Issues and Future Prospects. Williams & Wilkins; 1991. 3. WHO. Hepatitis B fact sheet N˚204. Impact of Immigration on HBV Immigration Numbers by Continent: 2002-2011 ~ 3.9 million Asians ~ 1.2 million Europeans ~ 924,000 South Americans HBsAg Prevalence ≥ 8% (high) ~ 907,000 2% to 7% (intermediate) Africans < 2% (low) 1. US Department of Homeland Security. Yearbook of immigration statistics: 2011. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.  Etiology HBV is transmitted by : vertical transmission (peri-natal), horizontal transmission: percutaneous and mucosal exposure to infectious blood or body fluids,/sexual exposure The risk of developing chronic HBV infection after acute exposure : 90% in newborns of HBeAg positive mothers 25–30% in infants and children under age 5 5% in adults. DIAGNOSIS  Goal of therapy in 2020 improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end- stage liver disease, HCC and death BUT... chronic HBV infection cannot be completely eradicated due to the persistence of (cccDNA) in the nucleus of infected hepatocytes=> HBV reactivation the HBV genome might favour oncogenesis and the development of HCC A more realistic endpoint is the induction of sustained or maintained virological remission. 2020  high viral load ongoing inflamation 4 Phases of Chronic HBV Infection Current Understanding of HBV Infection HBeAg Anti-HBe ALT activity HBV DNA Phase Immune Immune Inactive Reactivation Tolerant Clearance Carrier State Minimal Mild hepatitis Liver inflammation Chronic active and minimal Active inflammation inflammation and fibrosis fibrosis Optimal treatment times Yim HJ, et al. Hepatology. 2006;43:S173-S181. Copyright © 1999-2012 John Wiley & Sons, Inc. All Rights Reserved. During the treatment.... Nucleoside/Nucleotide Analogs Preferred agents Pegylated interferon (PEG-IFN)-alpha-2a (adults) or IFN- alpha-2b (children) – Adult dose 180 μg weekly; pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly Entecavir – Adult dose: Daily 0.5 mg (lamivudine-/telbivudine- naive persons) or 1.0 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily Tenofovir dipovoxil fumarate – Adult and pediatric (age ≥12 years) dose: 300 mg daily Tenofovir alafenamide – Adult dose only: 25 mg daily; no pediatric dosing Hepatitis B in 2020 HBV can cause chronic hepatitis, cirrhosis and HCC HBV vaccine prevents HBV infection and HCC HBV persists after HBeAg seroconversion and even after HBsAg clearance Safe treatments are available and are effective in suppressing but not in eradicating HBV, Outcomes of liver transplantation for HBV are as good as if not better than that for other liver diseases Global prevalence of HBV infection has declined but burden of HBV infection remains high  Hepatitis D (Delta) virus Hepatitis D virus is dependent on HBV for its reproduction. HDV co-infection is associated with more severe disease with a higher incidence of cirrhosis, hepatic decompensation and HCC Antigen of IgM anti HDV + viral load = Diagnosis PEG-IFN 180 μg weekly is the only effective treatment against HDV replication.