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Can One Pill A Day Keep Hepatitis B Away?. Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 30, 2009. TGH. Learning Objectives. To discuss new ‘normal’ values for ALT and define significant HBV DNA levels
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Can One Pill A Day Keep Hepatitis B Away? Scott K. Fung, MD, FRCPC Toronto General Hospital University of Toronto November 30, 2009 TGH
Learning Objectives • To discuss new ‘normal’ values for ALT and define significant HBV DNA levels • To briefly review antiviral treatment options for chronic HBV infection in 2009 • To illustrate indications for treatment of chronic hepatitis B and monitoring strategies using case studies
Quiz 1 2 3 4 • Wilson disease • Hereditary hemochromatosis • Chronic hepatitis B and HCC • Fatty liver
Liver Disease in Canada HBV Others Alcohol NAFLD HCV
Age-Standardized Mortality *Rate per 100,000 population, both sexes
Hepatitis B and HCC in Canada • Rate of HCC is rising in Canada and most Western countries • Related to immigration from HBV endemic parts of the world • No accurate data on overall prevalence of HBV and HCC in Canada • Estimated 1981-2005 using 2006 National census
Hepatitis B and HCC in Canada • Between 1981-2005, Canada accepted • 4 million new immigrants • 90% from HBV endemic areas (>3-7%) • HBsAg+ immigrants = 209,401 individuals • HBsAg+ nonimmigrants = 182,000indiv. • Overall prevalance in Canadian pop =1.3 % • Limited impact of HBV vaccine • ~500 immigrants will develop HCC per yr (0.22/100,000/yr) Leber et al, Can J Gastro 2009
All HBV Carriers are Potential Treatment Candidates Stop Rx not indicated Slow down Observe closely May need Rx later Go ahead with Rx
Stages of Chronic Hepatitis B Infection Lok, Gastroenterology 2007
HBeAg-negative CHB • Viral Load >3–4 log IU/mL • HBeAg-negative • pre-core / core promoter mutant • ALT intermittently abnormal • Biopsy • inflammation intermittent • fibrosis progression • Risk of complications (cirrhosis/ HCC) higher Adapted from Yim & Lok, Hepatology 2006; 43: S173
Disease Progression Chronic hepatitis HCC 10-20% Cirrhosis Liver Failure 15-40% Death or OLTx 20% Age 40 50 60 Years EASL Consensus Guidelines. J Hepatol 2003 Lok et al, Hepatology 2004
Complications of HBV HCC Ascites Varices
Danger Signs: Time To Worry • INR • Bilirubin Albumin Platelets Cirrhosis • Confusion • Jaundice • GI bleeding • Ascites
HBV DNA New unit of measurement for HBV DNA = logs IU/ml
HBV Viral load in Log Scale Log scales simplify large numeric differences in HBV DNA values Error of the test = 0.5 log IU Tripling of viral load = within the error of the test Following trends in HBV DNA important If in doubt, repeat testing to confirm
How High Can You Go? 1 = 100 = 1E0 10 = 101 = 1E1 100 = 102 = 1E2 1,000 = 103 = 1E3 10,000 = 104 = 1E4 100,000 = 105 = 1E5 1,000,000 = 106 = 1E6 10,000,000 = 107 = 1E7 100,000,000 = 108 = 1E8 1,000,000,000 = 109 = 1E9 10,000,000,000 = 1010=1E10 Low HBeAg-neg Medium HBeAg-pos High
REVEAL HBV Cirrhosis HCC HCC in HBeAg-negative patients with normal ALT Iloeje et al, JAMA 2006 Chen et al, Gastroenterology 2006
HBV DNA Report 4.3 E+7 43,000,000 7.4 log
“Normal” ALT Levels Upper Limit of Normal Male 53 U/L Female 31 U/L Yuen et al, Gut 2005
ALT and Liver Mortality Tai et al, Hepatology 2009
ALT Normal Values • Current upper limit of normal too high • New standard for ALT • Male <30 U/L • Female <19 U/L • Normal ALT does not exclude significant liver disease • Patients should not be denied antiviral treatment based on normal ALT Sherman et al, Can J Gastro 2007
Histology in HBeAg-positive CHB Note: This study population consisted of males over the age of 30 Yang et al, Chinese J Dig Dis 2002; 3: 150
Beware ‘Normal’ ALT Predictors of Sig. Fibrosis: Older Age Fluct. ALT Nguyen et al, Am J Gastro 2009
HBeAg-positive Patients HBeAg-positive HBV DNA <20,000 IU/mL(<105,200 copies/mL) HBV DNA >20,000 IU/mL(>105,200 copies/mL) ALT normal ALT elevated for 3–6 months ALT normal ALT elevated for 3–6 months No treatment. Monitor every 3 months with ALT and HBV DNA Rule out other causes of liver disease Monitor ALT every 3 months. Consider biopsy if age >35–40 years, and treatif significant disease Treat Based on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Selection of Specific Agents for HBeAg-positive CHB HBeAg-positive HBV DNA <20 million IU/mL(<105.2 million copies/mL) HBV DNA >20 million IU/mL(>105.2 million copies/mL) Standard interferon Pegylated interferon Adefovir Entecavir* Tenofovir*† Entecavir* Tenofovir*† *If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine †Approved since publication of the guidelinesBased on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
HBeAg-negative Patients HBeAg-negative HBV DNA <2,000 IU/mL(<10,520 copies/mL) HBV DNA >2,000 IU/mL(>10,520 copies/mL) ALT normal ALT elevated ALT normal ALT elevated No treatment. Monitor every 3 months for 1–2 years with ALT and HBV DNA Rule out other causes of liver disease Monitor ALT every 3 months, or consider biopsy, since ALT often fluctuates. Treat if significant disease. Long-term treatment required (oral agents) Treat. Long-term treatment required (oral agents) Based on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Selection of Specific Agents for HBeAg-negative CHB HBeAg-negative HBV DNA <20 million IU/mL(<105.2 million copies/mL) HBV DNA >20 million IU/mL(>105.2 million copies/mL) Pegylated interferon Adefovir Entecavir* Tenofovir*† Entecavir* Tenofovir*† *If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine †Approved since publication of the guidelinesBased on a conversion factor of 1 IU/mL = 5.26 copies/mL Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Comparison of Oral Therapy for Chronic Hepatitis B * Recommended as first-line therapy for HBV
HBV Treatment in Ontario in 2009 * Cirrhosis with DNA > 6 log IU/ml ** LAM virologic breakthrough and F3/F4 fibrosis or LAM-resistant HBV ├ Suboptimal response to LAM after 6 months
On Treatment Monitoring* • Frequency can be decreased once stable on treatment • (HBV DNA undetectable)
Patterns of Response Antiviral Drug 1.0 0 Primary nonresponse Virologic breakthrough -1.0 Change in HBV DNA (log10 IU/mL) Suboptimal response -2.0 -3.0 1 log Nadir -4.0 0 6 12 18 Mos Lok et al. Hepatology. 2007;45:507-539.
HBV Resistance Pathways 184/202/250 Pathway S Pre-existing resistant mutants ETV-R R R 180/204 Pathway LAM 236 Pathway 181 Pathway ADV LdT-R LAM-R ADV-R
HBV DNA Suppression HBeAg Loss Endpoints of Therapy HBsAg Clearance
Regression of Fibrosis Pre-Tx Adefovir Post-Tx
Antiviral Therapy for Advanced Liver Disease Liaw et al, NEJM 2004
Prevent HCC and Cirrhosis Decrease Liver Transplant True Goals of Therapy Lower Mortality
Tenofovir for Chronic Hepatitis B 8 Years Double Blind Open-label Tenofovir 300 mg Tenofovir 300 mg Study 102 N=250Study 103 N=176 RANDOMIZATION 2:1 Adefovir 10 mg Tenofovir 300 mg Study 102 N=125Study 103 N=90 Week 240 Liver Biopsy Week 72 Week 48 Liver Biopsy Pre-treatment Liver Biopsy Marcellin P et al., NEJM 2008
HBeAg (-) Study 102 % Patients with HBV DNA <400 c/mL Randomized Double Blind Open Label 91% [P=0.672] 89% On-Treatment Analysis 99% [P=0.166] 100% ~ 89% Patient Retention One patient was <400 copies/mL on FTC + TDF at Week 96. Long Term Evaluation ITT Analysis: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL excluded (N= 7) Marcellin P, et al., AASLD 2009; Oral # 146.
HBeAg (+) Study 103 % Patients with HBV DNA <400 c/mL Open Label Randomized Double Blind 78% 78% [P=0.801] On-Treatment Analysis 89% 85% [P=0.374] ~ 86% Patient Retention Five patients were <400 copies/mL at Week 96 on FTC + TDF. Long Term Evaluation: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL had their data excluded for visits after discontinuation (N = 8.) Heathcote J, et al., AASLD 2009; Oral # 153.
ALT Normalization Open Label TDF Randomized Double Blind 77% P= 0.014 61%
P = N S P = N S P = N S 2 7 % P = N S 3 0 3 0 2 6 % 2 5 2 5 2 1 % 2 2 % 2 1 % 2 1 % 1 8 % 2 0 2 0 % Patients % Patients 1 8 % 5 1 5 1 0 1 0 5 5 0 0 Week 48 Week 64 Week 48 Week 64 HBeAg Loss & Seroconversion TDF (Wk 48); TDF-TDF (Wk 64) ADV (Wk 48); ADV-TDF (Wk 64) HBeAg Seroconversion HBeAg Loss
Cumulative Probability* of HBsAg Loss in HBeAg (+) Patients 0.10 Switch to Open label TDF 6% TDF-TDF 6% ADV-TDF Cumulative Probability Function Estimate 0.05 0.00 0 12 24 36 48 64 80 96 Weeks on Study *Kaplan-Meier Heathcote, et al., EASL 2009; Poster #909.
Resistance Surveillance • Loss of viral response in 2 patients between Weeks 48 and 72 related to non-adherence documented in both patients • Viremic patients received combo TDF + FTC • Neither patient developed genotypic changes associated with AVR • No genotypic changes associated with AVR were detected up to 72 weeks
Mr. W. • 48 year old Chinese male patient • Known to be HBV ‘carrier’ • Otherwise healthy • History of liver CA in older brother • On no prescription medications or herbals • Routine diagnosis of HBV in China • No previous ‘Western’ medication for HBV
Labs AST Hb ALP ALT INR WBC Platelets Albumin Total bilirubin
Baseline Bloodwork 40 148 97 35 0.89 9.7 138 42 12