Lamivudine for Patients with hronic Hepatitis B and Advanced Liver Disease. From : New England Journal of Medicine

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1 Lamivudine for Patients with hronic Hepatitis B and Advanced Liver Disease From : New England Journal of Medicine Volume 351: , Number 15, Oct 7, 2004 馬 偕 紀 念 醫 院 一 般 內 科, 肝 膽 腸 胃 科 新 竹 分 院 陳 重 助 醫 師

2 前 言. Nature History of CHB, Liver cirrhosis ( compensated & Decompensated ) Hepatoma.Reference : 1. Semionars in liver disease / Vol 23, No 1, 2003, p Management of patients with decompensated HBV cirrhosis 2. Lamivudine treatment on diseease progression and development of liver cancer in advanced CHB Speaker : 廖 運 範 院 士, Dec. 27, 2003

3 HBV infection Infants Inapparent disease Recovery ( < 10%) 2%/yr, %/ 5-yr 30-40% Chronic hepatitis Cirrhosis 3-10%/yr Chronic infection ( > 90%) 0.8%/yr 60-70% Healthy carrier 0.1%/yr

4 81% / 5-year survival 70 %/4 year survival Candidates for liver transplantation 14% / 5-year survival

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6 Lamivudine in Chronic hepatitis B Goal of treatment in HBV-related chronic hepatitis 1. HBV suppression! / elimination? decrease pathogen & infectivity 2. Reduction of hepatic necro-inflammation hepatitis resolution & prevent decompensation 3. Prevention of disease progression hepatitis flares / decompensation cirrhosis and / or hepatoma 4. Improvement in survival & life quality

7 Lamivudine in Chronic hepatitis B with cirrhosis Speaker : 廖 運 範 院 士, Dec. 27, 2003 Nature course of liver cirrhosis if HBeAg (+)/ HBV-DNA (+) : 26 % AE / year if HBeAg (-)/ HBV-DNA (-) : 12 % AE / year the AE ( acute exacerbation) may induced decompensation Compensated liver cirrhosis : 5 years survival rate : Child A : 84 % Child B : 80 % Child C : 30 % Decompensated liver cirrhosis if HBeAg (+)/ HBV-DNA (+) : 14 % / 5- years survival if HBeAg (-)/ HBV-DNA (-) : 30 % / 5- years survival *** if Treated advanced liver disease & cirrhosis by Zeffix : % / 3-year survival

8 Lamivudine in Chronic hepatitis B with cirrhosis Speaker : 廖 運 範 院 士, Dec. 27, 2003 Zeffix may reverse fibrosis, improve life quality prevent progression, hepatic failure Zeffix is suggested in 1. Compensated cirrhosis with active HBV replication ALT > 1 ULN, or HBeAg (+), or HBV-DNA (+) 2. Any decompensated cirrhosis * Because the YMDD mutant ameliorates the histologic and clinical response, even induced hepatic failure continue Zeffix or shift to Adefovir immediately

9 全 民 健 保 加 強 慢 性 B 型 肝 炎 試 辦 計 劃 助 BsAg (+) 代 償 不 全 T 3 秒 ilirubin 3 mg/dl HBsAg(+) HBsAg(+) > 6 mon ALT>1X HBeAg (+) > 3 mon 器 官 移 植 ALT 5 x 癌 症 患 者 會 消 化 系 專 科 醫 師 HBsAg(+) > 6 mon HBeAg(+) > 3 mon 2x ALT 5 x 肝 切 片 HBcAg(+) 血 友 病 患 照 會 消 化 系 專 科 醫 師, 可 不 做 切 片 HBsAg(+) > 6 mon HBeAg (-) > 3 mon ALT 2 x ( 半 年 兩 次, 間 隔 三 個 月 ) 肝 切 片 HBcAg(+) 血 友 病 患 照 會 消 化 系 專 科 醫 師, 可 不 做 切 片

10 Study and design HB with HBeAg (+) HBeAg (-), but HBV-DNA (+) ( pre-core mutant ) or ALT > 1 x ULN Liver biopsy ( Dx by Ishak fibrosis score 4 ) ( 0 : no fibrosis 4~5 : advanced fibrosis 6: cirrhosis ) 651 patient ( fibrosis score 4 ~ 6 without decompensation ) into 2:1 Ratio 436 p t by Zeffix, 215 p t by placebo Primary end point by. Disease progression ( Child score 2, ascites, Albumin < 3.5, Bilurubin > 2 hepatic encephalopathy, hepatic decompensation ). SBP, CRI ( CCr < 50 ), EV or GV bleeding. Hepatoma

11 Child A 94 % Child B Not cirrhosis 67 % Cirrhosis 33 %

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13 Time to disease progression DB treatment and off-treatment follow-up 21% Percentage with disease progression Placebo P=0.001 Lamivudine 9% acebo (n=215) Time to disease progression (months) M

14 Time to Child-Pugh score increase DB treatment and off-treatment follow-up Percentage with Increase in Child-Pugh score Placebo 10% P=0.023 Lamivudine 4% Time to an Increase in Child-Pugh score (months) M lacebo (n=215)

15 Time to diagnosis of HCC DB treatment and off-treatment follow-up M Percentage with HCC Placebo P=0.047 Lamivudine 10% 5% Time to a diagnosis of HCC (months) acebo (n=215)

16 Time to disease progression by YMDD mutant status & Wild type Placebo (n=215) YMDDm (n=209) (49%) Wild Type (n=221) Placebo 21% 15 % with disease rogression 10 YMDD 13% 5 0 still Wild type % Time after randomisation (months)

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19 Patients in the Lamivudine group who had YMDD mutations were more likely to have an increased Child Pugh score than those without YMDD mutations (P<0.001), but they were less likely to reach an end point than were patients in the placebo group (P>0.05) P< P> 0.05

20 Discussion 1 The most important finding of this study is that lamivudine reduces the risk of liver complications for patients with chronic hepatitis B and cirrhosis or advanced fibrosis. The main reservation about the long-term use of lamivudine has been the emergence of YMDD mutations, which has occasionally been associated with severe, and even fatal, flares of hepatitis. In light of this uncertainty, the finding that treatment with lamivudine for a median period of 32 months reduces the rates of hepatic decompensation and hepatocellular carcinoma without increasing the number of serious adverse events is important.

21 Discussion 2 Even among patients who developed YMDD mutations clinical end points occurred less frequently than among patients receiving placebo. (next fig ) However, patients with YMDD mutations were more likely to have an increase in the Child Pugh score and to die for reasons related to clinical end points than were those patients who did not have YMDD mutations. The long-term effects of lamivudine on disease progression are not known. Since the present trial was started, treatment with a combination of adefovir dipivoxil and lamivudine has been shown to suppress replication of YMDD mutations and improve liver function in patients with hepatic decompensation. The adverse effects of YMDD mutations may be overcome by the addition of adefovir dipivoxil, but we did not assess this possibility in our population.

22 Time to disease progression by YMDD mutant status & Wild type Placebo (n=215) YMDDm (n=209) (49%) Wild Type (n=221) Placebo 21% 15 % with disease rogression 10 YMDD 13% 5 0 still Wild type % Time after randomisation (months)

23 Discussion 3 In summary, this multicenter, prospective, randomized, double-blind, placebo-controlled trial of lamivudine in patients with chronic hepatitis B and cirrhosis or advanced fibrosis showed that lamivudine decreased progression of the disease, thereby reducing clinically important complications.( hepatic decompensation,hcc) The emergence of YMDD mutations reduced the benefit of lamivudin but did not negate it, despite the occurrence of more end points due to decompensation among patients with YMDD mutations than among those without YMDD mutations. Our results provide the opportunity to develop strategies to achieve even better outcomes for patients with chronic hepatitis B and cirrhosis or advanced fibrosis by means of sustained viral suppression by minimizing or preventing the effects of drug resistance.

24 Conclusions Lamivudine reduces disease progression in cirrhotic CHB patients ( p=0.001) Lamivudine reduces the incidence of HCC (p=0.047) Lamivudine is safe and well tolerated in cirrhotic CHB patients for at least 3 years YMDD mutant emergence (49%) reduced the benefi in delaying disease progression

25 Summary of HBV with Zeffix treatment *HBeAg(+) with ALT > 5 ULN (seroconversion rate 65 %) *Acute exacerbation with decompensation ( early medication before Bil > 20 ; In practice, if Bilirubin >3mg/dl or PT prolong >3 seconds may start Zeffix as soon as possible *HBV (+) with organ transplantation recipient *HBV (+) cancer patient undergoing C/T * Decompensated cirrhosis waiting for liver transplantation ~*** Liver cirrhosis with decompensation ~ ** Liver cirrhosis( Child A,B ) afraid of relapse after Tx HBeAg(+) with ALT > 2~5 ULN (seroconversion rate 25 %) Pre-core mutant with elevated ALT