title: Chronic hepatitis B: what should be the goal for new therapies?
abstract: Chronic hepatitis B can currently be medically managed with either pegylated interferon-alpha (pegIFN-α) or one of the five nucleos(t)ide analog Direct Acting Antivirals (DAAs) that inhibit the hepatitis B virus (HBV) DNA polymerase. While pegIFN-α is effective in approximately one-third of the treated patients, the polymerase inhibitors significantly reduce viral load in the vast majority of those treated. However, neither pegIFN-α nor nucleosi(t)de analogs are capable of reliably eliminating the virus and achieving a cure. Moreover, the interferons and polymerase inhibitors are recommended by US, European and Asian professional society practice guidelines for use in only a subset of those infected with HBV. This subset is the population with the greatest levels of circulating viral DNA and abnormal liver function. Although this is the population at the highest risk for cirrhosis and liver cancer, those who fall outside the treatment guidelines, with low levels of viral replication and normal serum ALTs, may also benefit from antiviral therapy. The questions are thus: are new classes of drugs needed to manage chronic hepatitis B? Is a cure possible? Is a cure even necessary? It is therefore important to define the meaning of a cure and determine what the goals of new therapies should be. In this article, we address those questions and propose two operational definitions of medically attainable cures. The first is a "functional cure" based on the clinical outcome, in which the patient's life expectancy becomes the same as that of an individual who has resolved his HBV infection without therapy. Because such an outcome cannot be measured over the short term, we also define an "apparent virological cure," based on the stable off-drug suppression of HBV viremia and antigenemia and the normalization of ALTs and other laboratory tests. We suggest that such a virological cure should be the goal of future therapeutics in all patients with chronic hepatitis B. The extent to which a virological cure predicts a functional cure will only be determined by long-term follow-up.
authors: Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA. Timothy.Block@drexelmed.edu
authors: Timothy M
authors: TM
authors: Block
authors: Robert
authors: R
authors: Gish
authors: Haitao
authors: H
authors: Guo
authors: Anand
authors: A
authors: Mehta
authors: Andrea
authors: A
authors: Cuconati
authors: W
authors: W
authors: Thomas London
authors: Ju-Tao
authors: JT
authors: Guo
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents
references: J Virol. 1995 Sep;69(9):5697-704
references: 7543585
references: Lancet. 2006 Sep 9;368(9539):938-45
references: 16962883
references: Aliment Pharmacol Ther. 2008 Nov 1;28(9):1067-77
references: 18657133
references: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1139-44
references: 15657132
references: J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:123-30
references: 21199523
references: N Engl J Med. 2004 Oct 7;351(15):1521-31
references: 15470215
references: J Hepatol. 2009 Feb;50(2):227-42
references: 19054588
references: Hepatology. 2011 Aug;54(2):E1-9
references: 21793018
references: Gastroenterology. 2010 Jul;139(1):120-9.e18
references: 20399780
references: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4398-402
references: 8633078
references: J Virol. 2010 Aug;84(16):8308-15
references: 20519397
references: J Viral Hepat. 2004 Sep;11(5):443-7
references: 15357650
references: Cancer. 1988 May 15;61(10):1942-56
references: 2834034
references: Clin Infect Dis. 2008 Jan 1;46(1):78-84
references: 18171217
references: J Gastroenterol Hepatol. 2011 Feb;26(2):221-7
references: 21070361
references: Hepatology. 2009 Sep;50(3):661-2
references: 19714720
references: Gastroenterology. 2011 Jan;140(1):132-43
references: 20955704
references: J Hepatol. 2006 Feb;44(2):422-31
references: 16364492
references: Intervirology. 2002;45(4-6):237-50
references: 12566706
references: Int J Clin Pract. 2012 Apr;66(4):342-55
references: 22420497
references: Science. 2011 May 13;332(6031):784-5, 787-9
references: 21566173
references: J Gastroenterol Hepatol. 2011 Oct;26(10):1527-35
references: 21557773
references: J Virol. 2009 Jan;83(2):847-58
references: 18971270
references: J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:138-43
references: 21199525
references: Annu Rev Pathol. 2006;1:23-61
references: 18039107
references: Clin Gastroenterol Hepatol. 2006 Feb;4(2):233-48
references: 16469685
references: N Engl J Med. 2008 Oct 2;359(14):1486-500
references: 18832247
references: Antimicrob Agents Chemother. 2012 Aug;56(8):4277-88
references: 22644022
references: J Viral Hepat. 2004 Mar;11(2):97-107
references: 14996343
references: Virology. 2009 Oct 10;393(1):84-90
references: 19683778
references: Gastroenterol Hepatol (N Y). 2010 Mar;6(3 Suppl 6):1-16
references: 20567570
references: Clin Liver Dis. 2007 Nov;11(4):685-706, vii
references: 17981225
references: Hepatology. 2010 Nov;52(5):1611-20
references: 20931556
references: J Viral Hepat. 2012 Mar;19(3):213-9
references: 22329376
references: Antimicrob Agents Chemother. 2007 Dec;51(12):4427-37
references: 17875990
references: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6669-74
references: 15100412
references: J Clin Invest. 2012 Feb;122(2):529-37
references: 22251702
references: J Virol. 2007 Apr;81(8):4215-25
references: 17287266
references: Hepatology. 1999 Sep;30(3):770-4
references: 10462384
references: Gastroenterology. 2005 Jun;128(7):1890-7
references: 15940624
references: Hepatology. 2010 Jun;51(6):1933-44
references: 20512987
references: Hepatology. 2006 Sep;44(3):675-84
references: 16941693
references: J Virol. 2002 Jun;76(11):5305-14
references: 11991959
references: J Virol. 2000 May;74(10):4483-94
references: 10775584
references: Arch Intern Med. 2000 Nov 27;160(21):3227-30
references: 11088082
references: Gastroenterology. 2004 Jun;126(7):1750-8
references: 15188170
references: Hepatology. 2010 Oct;52(4):1242-50
references: 20658465
references: J Virol. 2003 Jan;77(1):68-76
references: 12477811
references: Antivir Ther. 2013;18(2):229-35
references: 22914436
references: Gut. 2012 Mar;61(3):333-6
references: 22147510
references: Hepatology. 2001 Nov;34(5):1012-20
references: 11679973
references: J Hepatol. 2011 Nov;55(5):1121-31
references: 21718667
references: Liver Int. 2010 Oct;30(9):1379-86
references: 20738778
references: Hepatology. 2009 May;49(5 Suppl):S156-65
references: 19399803
references: PLoS One. 2012;7(6):e39179
references: 22761734
references: Hepatology. 2013 Feb;57(2):438-40
references: 22815252
references: Clin Gastroenterol Hepatol. 2012 Mar;10(3):297-302
references: 21893131
references: N Engl J Med. 2004 Mar 11;350(11):1118-29
references: 15014185
references: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5050-5
references: 17360406
references: Hepatology. 1999 Jun;29(6):1863-9
references: 10347131
references: J Virol. 2009 Sep;83(17):8396-408
references: 19535448
references: J Viral Hepat. 2011 Jun;18(6):377-83
references: 21143343
references: Am J Gastroenterol. 2006 Aug;101(8):1797-803
references: 16817842
references: Hepatology. 2009 Apr;49(4):1151-7
references: 19115222
references: Science. 2009 Mar 6;323(5919):1304-7
references: 19265012
references: Hepatol Int. 2008 Sep;2(3):263-83
references: 19669255
references: J Hepatol. 2010 Aug;53(2):348-56
references: 20483498
references: Clin Infect Dis. 2012 Jul;55 Suppl 1:S16-24
references: 22715209
references: J Gastroenterol Hepatol. 2010 Sep;25(9):1498-506
references: 20796146
references: Science. 1999 Apr 30;284(5415):825-9
references: 10221919