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Chiang CJ, Yang YW, Chen JD, You SL, Yang HI, Lee MH, Lai MS, Chen CJ

Hepatology 2014 Dec 5

• Dr. Tung Yau Man Stephen

Associate Consultant, KWH Journal Review , HKASLD 15th January, 2015

Introduction

 There were estimated 350 million people

with chronic HBV infection and 170 million people infected by HCV worldwide

 Taiwan CDC : 2.5M CHB patients and 0.7M

HCV infected people in 2012.

 Cohort study : lifetime risk of cirrhosis and

HCC was 42% and 22% for CHB patients

 Cumulative lifetime risk of HCC was 20% for

CHC patients.

 A national viral hepatitis therapy program

was launched in Taiwan in October 2003.

 This study aimed to assess the impact of the

program on reduction of end-stage liver disease burden.

 Profiles of national registries of households,

cancers and death certificates were used to derive incidence and mortality of end-stage liver diseases from 2000 to 2011.

Reimbursement Program

 CHB:

 IF-a and lamivudine reimbursement since 10-

2003

 Peg IFa since 11-2005; adefovir as rescue since

9-2006

 Entecavir and telbivudine since 8-2008  Tenofovir since 6-2011

 CHC:

 PegIF and ribavarin 10-2003

 The age-gender-adjusted incidence and

mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases and cirrhosis

• f adults aged 30-69 years were compared

before and after launching the program using Poisson regression models.

 A total of 157,570 and 61,823 patients (15-

25% of the eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011

Method

 National health insurance 1995- mandatory,

99% resident

 Eligibility for reimbursement ( see table)  Liver cirrhosis defined by sonography in the

presence of either splenomegaly or esophageal/ gastric varices, or by histology

 Since 2009, Eligible CHB patients received

36m , instead of 18m

 HBeAg+ patients could receive another one

year medication if seroconversion of HBeAg was successfully documented during the 36m treatment period.

 For HepC treatment, reimbursed

therapeutic course could be extended from 16 wk to 24 wk and even to 48 wk based on the viral kinetic response to therapy.

Eligibility Criteria of antiviral therapy for CHB & CHC

T 1.Eligibility Criteria and 1st line antiviral therapy for CHB & CHC

• F1. Cumulative numbers of anti-

HBV/HCV therapy

Mortality and incidence rates derived from National Registration Profiles

 Death and migration event must be

registered in the governmental household registration officers and regularly checked by registration officers.

 Year end population obtained by annual

reports of demographic statistics.

 All death certificate coded by medical

registrars according to ICD9.

 National cancer registry since 1979  HCC coded under ICD-O-3 code C220.

Statistical Analysis

 Mortality and incidence rates were derived

by diving the number of deaths or incident cases by the number of population.

 Stratified by gender and age (30-39,40-49,

50-59 and 60-69 years ) groups.

 Poisson regression models, rate ratios with

95% confidence intervals were calculated.

 2 sided test, p<0.05 was considered

statistically significant.

Result

 There were 42,526 chronic liver diseases and

cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person- years from 2000 to 2011.

 Male gender and elder age were associated with a

significantly increased risk of chronic liver diseases and cirrhosis and HCC.

 The mortality and incidence rates of the end-stage

liver diseases decreased continuously from 2000- 2003 (before therapy program) through 2004-2007 to 2008-2011 in all age and gender groups.

F2 . CLD and cirrhosis mortality HCC mortality

HCC incidence rate

• T2. Mortality and Incidence rates and Adjusted rate

ratio of CLD, cirrhosis and HCC

 Significant decreasing trend of mortality and

incidence rates in both genders.

 Reduction in mortality rates of CLD and

cirrhosis and HCC , and incidence rates of HCC was more striking in both genders in 2008- 2011.

 The decreases in adjusted RR were more

striking for mortality rates than incidence rates.

 Decreasing trends in age adjusted rate ratios

were more striking in females than males.

Gender adjusted rate ratios of CLD, cirrhosis and HCC among four 10-year age groups.

 The decreasing trends in gender adjusted

mortality and incidence rate ratios were consistently observed in all 4 age groups.

• T4. Adjusted RR of CLD, cirrhosis and HCC

in adults aged 30-69 years from 2000-2011

 Male gender was associated with a 4 fold

risk of age period adjusted mortality and incidence rates of end stage liver diseases.

 Increasing age was significantly associated

with an increasing trend of HCC incidence and mortality

Discussion

 Significant reduction of end stage liver

disease burden resulted from a national viral hepatitis therapy program at the population level.

 Showed the decreasing trend of rate ratios

after adjustment for age and gender for all age groups in both genders.

 More significant reduction of 12-19 % in incidence

and mortality of HCC, and mortality of CLD and cirrhosis was observed after 2007, when more antivirals including entecavir and tenofovir for CHB were approved .

 More striking reduction in 08-11 , as result from

latent period between reimbursed therapy and reduced risk of end stage liver diseases.

 May prevent the HCC recurrence and therefore the

reduction in HCC mortality was greater than the HCC incidence reduction.

 More striking reduction in end stage liver

diseases in females and elderly - higher proportion of hepatitis C, which may be more effectively treated by the combination therapy than CHB.

Limitation

 Pre/post treatment HBV DNA level , HCV

RNA levels

 Type and duration of anti viral agents  Cost effectiveness  Confounding factors : Eligible untreated

patients, other factors that may have reduce the mortality, e.g. surgical Mx, reduced post

• perative decompensation, HCC surveillance

 Lack of control group

HCC cases by year (by diagnosis code search)

100 200 300 400 500 600 0 - 14 15 - 44 45 - 49 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 80 - 84 85+ 2008 2011 2014

Statistics from HA

HA HCC Death Cases by year

(by diagnosis code search)

50 100 150 200 250 300 350 0 - 14 15 - 44 45 - 49 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 80 - 84 85+ 2008 2011 2013 2014

Summary of HCC Case# and death# by diagnosis code search

 HCC Death Cases

Age 2008 2011 2014

0 - 14 4 13 10 15 - 44 160 167 147 45 - 49 188 160 122 50 - 54 316 325 288 55 - 59 372 445 515 60 - 64 341 507 519 65 - 69 360 379 459 70 - 74 357 390 382 75 - 79 294 381 406 80 - 84 187 261 337 85+ 98 143 190 Total 2678 3172 3375

HCC Total Cases by year

Age

2008 2011 2013

2014 0 - 14 1 3 3 2 15 - 44 131 103 80 61 45 - 49 146 101 61 48 50 - 54 246 220 148 104 55 - 59 290 287 245 171 60 - 64 259 316 273 162 65 - 69 292 269 203 141 70 - 74 304 298 221 145 75 - 79 273 302 229 155 80 - 84 179 224 206 167 85+ 96 129 135 127 Total 2217 2252 1804 1283

Anti-viral treatment patient headcount 2014

Adefovir 1420 Entecavir 22800 Lamivudine 4700 Telbivudine 2950 Tenofovir 4460 Total drug expenditure ~ 381 M