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Nguyen, MD, MAS Assistant Professor of Medicine Division of Gastroenterology & Hepatology Liver Transplant Program Stanford University Medical Center 9/15/2006$S HChronic Hepatitis B6Disease burden in Asian Americans Natural history: HBV DNA levels ALT levels Impact of treatment on disease progression Rationale for screening for hepatocellular carcinoma (HCC)F3f3e&HBV Disease Burden in Asian-Americans'' Hepatitis B Prevalence*8Low overall U.S. prevalence: 0.3% Asians: ~ 10-13% 938*  Etiology of HCC in Asians HCC - California6 4Impact of HBV DNA and ALT Levels on Disease Outcomes  1HBV DNA Levels, Disease Progression and HCC Risk22@  Impact of Viral LoadZHigh viral load: Liver inflammation1 Cirrhosis2 Liver failure3 HCC4 Liver-related deaths4I          ;Reduction in viral load: Liver disease progression3,5 HCC3 d"     -HBV DNA Associated with Increased Risk of HCC..(Likelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNA Risk associated with increasing HBV DNA levels These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication<p0xp0x >HBV DNA levels and Risk of Cirrhosis and HCC REVEAL-HBV Study ?=$Large population-based prospective, long-term cohort study (Taiwan) Mean follow-up: 11 years (> 40,000 person-years) Cirrhosis analysis1,2: n=3582 365 cases (10%) HCC analysis3: n=3653 164 cases (4.5%) l     3HBV DNA Levels Predict Risk of Developing Cirrhosis4* 3 3HBV DNA Levels Predict Risk of Developing Cirrhosis 43`3  EViral Load Is the Main Predictor of Cirrhosis Regardless of Serum ALT"FE( (E  -HBV DNA Levels Predict Risk of Developing HCC .*$$- ,Dose-Response Relationship: HBV DNA and HCC:HBV DNA Levels are Associated With Clinical Outcomes (HCC);;b$ ;  1REVEAL-HBV Study: Cirrhosis Analysis Conclusions 20(HBV DNA level e" 104 copies/mL is associated with significant risk for progression to cirrhosis - regardless of HBeAg status or serum ALT level1,2 Elevated serum HBV DNA is a strong predictor of cirrhosis in HBV-infected patients1,2 According to a prediction model, HBV DNA is the most significant modifiable risk factor3hA z R P!*REVEAL-HBV Study: HCC Analysis Conclusions++(HBV DNA level e" 104 copies/mL is a strong and significant predictor of HCC  independent of HBeAg status, serum ALT level, and presence of cirrhosis1 According to a prediction model, HBV DNA is the most significant modifiable risk factor2 Patients with persistently elevated serum HBV DNA levels were at highest risk for development of HCC1 lV  W d "6REVEAL-HBV Study: HCC Analysis Conclusions (continued)77(Potent antiviral agents that can decrease HBV DNA to undetectable levels (regardless of HBeAg status and ALT levels) may reduce the risk for HCC HBeAg negative patients with normal ALT and elevated HBV DNA, representing an increasing majority of CHB patients, should be further studied*u#*Impact of Treatment on Disease Progression++@ $%SLamivudine and Disease Progression and HCC incidence in Advanced HBV (stage III/IV)TTProspective, multicenter, randomized, double-blind, placebo-controlled, parallel group study HBeAg+ or HBeAg- Lamivudine 100 mg qd (n=436) vs. placebo (n=215) Designed to be d" 5 year study; terminated at 2nd interim analysis due to lamivudine superiority&1HBV DNA Suppression Reduces Cirrhosis Progression1 '/ HBV DNA Suppression Reduces HCC Incidence Rate00(/ ( ConclusionsLamivudine reduces risk of liver complications for patients with CHB and cirrhosis or advanced fibrosis by about 50% over 32 months Lamivudine also reduces HCC incidence rate by almost 50% YMDD mutations reduced benefit of lamivudine, but did not negate it)Summary0HBV DNA is an essential marker for predicting risk for complications Viral suppression is associated with improved treatment outcomes in patients with advanced fibrosis. Emerging potent antiviral therapies provide the potential for more effective treatment response and prevention of complications of CHB110 P4&Screening for Hepatocellular Carcinoma'' Q3+Screening for HCC Consensus Recommendations ,  1Anchorage, Alaska: AFP and US Yearly: HBsAg carriers age >35 years or FH of HCC Every 6 months: chronic hepatitis B with cirrhosis 2Milan, Italy: AFP and US every 6 months Cirrhosis of any cause 3Barcelona, Italy: AFP and US every6 months Cirrhotic patients who are eligible to available treatments 1McMahon, J Natl Cancer Inst 1991 2Colombo. J Hepatol 1992 3Bruix, J Hepatol 2001 @ZeZ)ZZ,Z<ZcZ e ( +             '        =NV6HCC: Screening Tests(Imaging studies Ultrasound* Computed tomography No significant differences between spiral CT and MRI Stoker J, Gut 2002 Blood tests Alpha-fetoprotein* Des-gamma-carboxy prothrombin Hepatoma-specific isoforms of alpha-fetoproteinZjZ ZbZ K`b`   O`>W7Range of AFP levelsX8[Changes in sensitivity and specificity of AFP for diagnosis of HCC using various cut-offs \Z]=UDCP (PIVKA II) Des-carboxy prothrombin (prothrombin induced by Vitamin K absence II)&VF(>  " :(Screening US Sensitivity and Specificity) &Study Sensitivity Specificity Okazaki, 1984 86% 99% Maringhini, 1988 90% 93% Tremolda, 1989 85% 50% Dodd, 1992 50% 98% Pateron, 1994 78% 93% Zhang, 1999 84% 97%"">; )*;) HCC: Screening Strategies and Frequency  *) &US q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S. Rationale for 6-month screening interval Doubling time: median = 6 mo *=!WHO Principles of Screening&<Screening improves survival Cost of screening is acceptable==!F*HCC Screening: clinical studies  "Study, year, location Improved survival McMahon, 2000, Alaska, US Yes Wong, 2000, Hawaii, US Yes Yuen, 2000, Hong Kong Yes Bolondi, 2001, Italy Yes Chen 2002, Taiwan Yes 8Z)!5H,Lead-Time BiasI-Length/Prevalence BiasJ.Pseudo-Disease^>RCT for HCC ScreeningN = 18,816 persons, aged 35-59, in Shanghai History of chronic hepatitis (HBsAg+ in 17,250 or 92%) Male: Female ratios ~ 1.7 for both groups Screening group = 9373---AFP, US every 6 months Control group = 9443---No screening, "usual care and continued to use the health care facilities" Recruitment: 1/93 - 12/95 Screening: ended 12/97 End of follow-up: 12/98 (38,444 person-years) ,`J2_?7Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-2288, `@7Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-2288, aA7Zhang BH et al, J Cancer Res Clin Oncol 2004;130:417-2288, E).Cost-Effectiveness of Screening: Other Cancers&/.b &. dOthers $/life-year saved Pap smear 15,000  30,000 Colonoscopy 28,143 Flexible sigmoidoscopy 74,032 Fecal occult blood testing 81,678 Mammography 30,000  100,000.f b &Z   L G+#Cost-Effectiveness of HCC Screening$#$Real-life studies with cost information: Bolondi, Gut 2001 Child-Pugh A and B; AFP/US q 6 mo Study period: 1989-1997 $17,934 per treatable HCC $112,993 per QALY gained Results may not be generalizable to US patients: cost not based on actutal cost and no OLT for age > 60. Yuen, Hepatology 2000 $1,167 annually to detect 1 HCC $1,667 annually to detect 1 treatable HCC Mostly hepatitis B patients Cost based on 25$/AFP and 100$/US ;ZZZZZZ)  >) #K/CHCC Screening Role of Cost-effectiveness Analysis/Decision Analysis:D $$RCT is not feasible due to ethical issues Observational or cohort studies require an extremely long follow-up period and affected by: Lead-time bias Length-bias Pseudo-disease phenomenon :" 65L0BHCC Screening: Cost-effectiveness Analysis (AFP/US every 6 months)<C f4Study Patients CE ratio (< 50,000$/QALY) Sarasin, 1996 Child A No No OLT Everson, 2000 OLT/LDLT Yes (abbreviated) Sarasin, 2001 OLT/LDLT Yes *OLT > LDLT after 3.5 months Patel, 2002 HCV cirrhosis Yes (abstract) OLT/LDLT *Main cost burden is cost of OLT and not with screening cost Lin, 2004 HCV cirrhosis No *Yes if US q12 months only `Z8|6B!$M1Screening for HCC: Summary(HCC is an important cause of mortality in patients with HBV and in Asians. 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Gastroenterol 2006;130 (3):678-86.240    3 H X 0޽h ? 33y___PPT10Y+D=' = @B +u  ``(  ` ` s 0e0e #" 0e `}     ` <\   3Iloeje UH et al. Gastroenterol 2006;130 (3):678-86.240    3  `0  fA ? "` `   ` T 3>?"6@ NNN?N/wd OHBV DNA levels:$0(CH ` 0޽h ? 33___PPT10i.<С1+D=' = @B +@  g _ h (  h~ h s *R  `}    h <4 rSf AIloeje UH et al. J Hepatology 2005;42(suppl 2):180. Abstract 497.8B0 %A  h HA  ?     h < a =5 \<300 0   h <9a Z< 5 |300  <1040 0      h < 9a  5 104  <105N 0       h <09a 5 105  <106N 0        h B(9a _5  e" 106D0 '    h <49OZ6 iHBV DNA (copies/mL)0     h <i 6Cirrhosis incidence /100,000 Person-Years of Follow-up070 $6 F a[5  h [a5  h <8i[U !ALT <1 x ULN, n = 3542, P < .001 J"0 ! \ h <8s;~5 >ALT e"1 x ULN, n = 232, P < .001^ 0 '(  f h 6a2n h 0"`aH h 0޽h ? 33y___PPT10Y+D=' = @B +. K0 --88p--(  p~ p s * `}   _)~ |  p# #"*jX88h|  p <x?o/ |  6.1 (2.9-12.7)! 0  @` p B8??/ o  j1152  @` p B? / ?  h79  @` p BL?/   j6858  @` p BՁ?/   i627  @`  p <ށf?/   re"1.0x1060 &,, @`"  p <@؁?o |/  6.6 (3.3-13.1)! B  @`  p B?? o/  i962  @`  p B$? ?/  h37  @`  p B?  /  j3845  @` p BD)? /  i349  @` p <L+f? /  1.0 9.9x105>  ,,,   @`  p <4??o|  2.3 (1.1 4.9) B   @` p BG??o  i297  @` p B4P? ?  h22  @` p BY?  j7404  @` p Bb?  i643  @` p <f?  1.0 9.9x104.  ,,   @` p <?og| 1.1 (0.5 2.3)   @` p B0??go i111  @` p B? g? h15  @` p B?g  l13,518  @` p B?g j1161  @` p <Hrf?g 300 9.9x103&      @` p <H_?o|g {1.0 (reference)  @` p Bt ??og i108  @` p B ? ?g h11  @` p B~? g l10,154  @`  p Bl~?g i873  @` !p <~f?g p <300 (LOQ)     @` "p 6"~?o| Adjusted HR* (95% CI)@    @` #p <-~??o Incidence rate (per 100,000)  @` $p <6~? ? Number of subjects with HCC  @` %p <7~?  ~Person-year of follow-up  @` &p <H~? zCohort member number  @` 'p 6J~f? 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