Lamivudine for Patients with Chronic Hepatitis B and Advanced Liver Disease

From : New England Journal of Medicine Volume 351:1521-1531, Number 15 , Oct 7 , 2004

馬偕紀念醫院 新竹分院

一般內科 , 肝膽腸胃科 陳重助 醫師

前言A . Nature History of CHB ,

Liver cirrhosis ( compensated & Decompensated )Hepatoma

B .Reference :1. Semionars in liver disease / Vol 23 , No 1, 2003, p89-100

Management of patients with decompensated HBV cirrhosis

2. Lamivudine treatment on diseease progressionand development of liver cancer in advanced CHB

Speaker : 廖運範 院士 , Dec. 27, 2003

HBV infection

Infants

Inapparent disease

Recovery( < 10%)

Chronic infection( > 90%)

Chronic hepatitisHealthy carrier

Cirrhosis

HCC

60-70%30-40%

3-10%/yr0.1%/yr

0.8%/yr

Kao JH. Intervirology (in press).

2%/yr , 15-20 %/ 5-yr

Candidates for liver transplantation70 %/4–year survival

14% / 5-year survival

81% / 5-year survival

Lamivudine in Chronic hepatitis B

Goal of treatment in HBV-related chronic hepatitis1. HBV suppression ! / elimination ?

decrease pathogen & infectivity2. Reduction of hepatic necro-inflammation

hepatitis resolution & prevent decompensation3. Prevention of disease progression

hepatitis flares / decompensationcirrhosis and / or hepatoma

4. Improvement in survival & life quality

Lamivudine in Chronic hepatitis B with cirrhosisSpeaker : 廖運範 院士 , Dec. 27, 2003

Nature course of liver cirrhosisif 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 & cirrhosisby Zeffix : 70-80 % / 3-year survival

Placebo : 40 % / 3-year survival

Lamivudine in Chronic hepatitis B with cirrhosisSpeaker : 廖運範 院士 , Dec. 27, 2003

Zeffix may reverse fibrosis , improve life quality prevent progression , hepatic failure

Zeffix is suggested in1. 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

全民健保加強慢性B型肝炎試辦計劃.

陳重助

1 2 3 4 5HBsAg (+)&代償不全

HBsAg(+) HBsAg(+)> 6 mon

HBsAg(+)> 6 mon

HBsAg(+)> 6 mon

PT≧3秒 ALT>1X HBeAg (+) > 3 mon

HBeAg(+) > 3 mon

HBeAg (-) > 3 mon

Bilirubin≧ 3 mg/dl 器官移植 ALT≧ 5 x

2x≦ ALT ≦ 5 x

ALT≧ 2 x (半年兩次，間隔三個月)

　

癌症患者　 肝切片

HBcAg(+)肝切片

HBcAg(+)　

會消化系專科醫師

　血友病患照會消化系專科醫師,可不做切片

血友病患照會消化系專科醫師,可不做切片

Study and design CHB 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 by1. Disease progression

( Child score ≧ 2, ascites , Albumin < 3.5 , Bilurubin > 2hepatic encephalopathy , hepatic decompensation )

2. SBP , CRI ( CCr < 50 ) , EV or GV bleeding3. Hepatoma

Child A 94 %

Child B

Not cirrhosis 67 %

Cirrhosis 33 %

Time to disease progressionDB treatment and off-treatment follow-up

Percentage with disease progression

Time to disease progression (months)Placebo (n=215) Lamivudine (n=436)

Lamivudine

Placebo

P=0.001

21%

9%

198417

173385

43122

M

Time to Child-Pugh score increaseDB treatment and off-treatment follow-up

Percentage with

Increase in

Child-Pugh score

Time to an Increase in Child-Pugh score (months)

Lamivudine

Placebo

P=0.023

10%

4%

198417

Placebo (n=215) Lamivudine (n=436)

173385

43122

M

Time to diagnosis of HCCDB treatment and off-treatment follow-up

Percentage

with HCC

Time to a diagnosis of HCC (months)

Lamivudine

Placebo

P=0.047

10%

5%

Placebo (n=215) Lamivudine (n=436)

198417

173385

43122

M

Wild Type (n=221)YMDDm (n=209) (49%)

Time after randomisation (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Time to disease progressionby YMDD mutant status & Wild type

% with disease

progression

Placebo (n=215)

YMDD

still Wild type

Placebo

5%

13%

21%

•

•

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

P< 0.001 P> 0.05

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 withlamivudine for a median period of 32 months reduces the rates of hepatic decompensation and hepatocellular carcinoma withoutincreasing the number of serious adverse events is important.

Discussion – 2Even 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.

Wild Type (n=221)YMDDm (n=209) (49%)

Time after randomisation (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Time to disease progressionby YMDD mutant status & Wild type

% with disease

progression

Placebo (n=215)

YMDD

still Wild type

Placebo

5%

13%

21%

Discussion – 3In summary, this multicenter, prospective, randomized, double-blind,

placebo-controlled trial of lamivudine in patients with chronichepatitis 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 lamivudinebut did not negate it, despite the occurrence of more end points due to decompensation among patients with YMDD mutations thanamong 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.

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 benefit

in delaying disease progression

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