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Effects of Lamivudine on Disease Progression and Development of Liver Cancer in Advanced Chronic Hepatitis B: a prospective double-blind placebo controlled clinical trial
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Reported by Jules Levin
Yun-Fan Liaw, from Chang Gung University, Taipei, Taiwan, GlasoSmithKline, and colleagues reported on this study at AASLD 2003.
Summary:
The authors concluded lamivudine reduces disease progression in cirrhotic chronic HBV patients (p=0.001). Lamivudine may reduce HCC (p=0.047). Lamivudine is safe and well tolerated in cirrhotic CHB patients for at least 3 yrs. YMDD mutation emergence (49%) reduced the benefit in delaying disease progression. Treat early (CP≤6) for optimal benefit
Liaw provided this background. Cirrhosis due to chronic hepatitis B is a common cause of liver failure, hepatocellular carcinoma (HCC) and a major cause of mortality in the Asia-Pacific region. Lamivudine (LAM) markedly suppresses viral replication and this confers histological improvement and improved liver function. However, longer term use leads to viral breakthrough in some patients due to emergence of YMDD variants, so the net impact on clinical disease progression in HBV related cirrhosis has been unclear.
The aim of this study is to compare the long term efficacy and safety of lamivudine (LAM) and placebo (PLB) in the progression of HBV related cirrhosis.
Patients were >16, serum HBsAg+ for >6 months, HBeAg and/or HBV-DNA+ at screening, Ishak fibrosis score ≥4 (reviewed by independent pathologist), and lamivudine treatment naïve.
Patients were excluded for HCC (liver cancer); ALT >10 ULN/history of acute exacerbation leading to transient decompensation; HCV, HDV, or HIV; decompensated liver disease; serious concurrent illness; autoimmune hepatitis; planned/previous liver transplant; pancreatic amylase and/or lipase >2 ULN; Cr >ULN; Hemoglobin < 8 g/dl; WBC < 1.5x 109/L; platelet ≤50x109/L.
Patients with histologically confirmed compensated HBV related cirrhosis were randomised 2:1 to LAM 100mg/day or placebo for up to 5yrs. The primary endpoint was time to disease progression defined as Child-Pugh score increase ≥ 2, development of HCC, spontaneous bacterial peritonitis, bleeding upper GI varices or liver-related death, renal insufficiency. Following blinded treatment, open label lamivudine was offered to eligible patients (eg. those reaching a clinical endpoint). An independent data safety monitoring board (DSMB) monitored study progress at interim analyses using prospectively defined stopping criteria.
436 patients received LAM, 215 placebo. Average age was 44. 85% were men. 98% were Asian. 80% had ALT >ULN. HBeAg+ 58%. HBV-DNA+ 80%. Patient characteristics at baseline were comparable between the two arms.
At the recommendation of the DSMB, the study was terminated at the second interim analysis, due to a significant difference in the number of endpoints between the two treatment groups, and patients were offered open label lamivudine. Median treatment exposure was 32.4 (range 0.0-42.1) months.
RESULTS
72 patients reached clinical endpoints - 33/436 (8%) of patients on LAM and 38/215 (18%) on placebo (hazard ratio 0.45, 95% CI 0.28 to 0.73, p=0.001).
HBeAg seroconversion: 60 (14%) on LAM 100mg and 7 (3%) on placebo.
Consent withdrawn, lost to follow-up: 5% on LAM and 10% on placebo.
Adverse event: 2% on LAM and <1% on placebo.
DISEASE PROGRESSION DURING DOUBLE-BLIND TREATMENT AND OFF-TREATMENT FOLLOW-UP
Overall disease progression was 7.8% on LAM and 18% on placebo (p=0.001). Increase in C-P score (progression of disease) was 3.4% on LAM and 8.8% on placebo (p=0.023). HCC occurred in 3.9% on LAM and 7.4% on placebo (p=0.047). Bleeding varices occurred in 0.5% on LAM and 1.4% on placebo. Renal insufficiency occurred in 0.5% on LAM ans 0 on placebo.
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LAM |
Placebo |
Hazard Ratio |
P |
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n=436 |
n=215 |
95% |
CI |
| Overall disease progression |
7.8% |
18% |
0.45 (0.28-0.73) |
0.001 |
| Increase in C-P score |
3.4% |
8.8% |
0.45 (0.22-0.90) |
0.023 |
| Hepatocellular carcinoma |
3.9% |
7.4% |
0.49 (0.25-0.99) |
0.047 |
| Renal insufficiency |
0.5% |
0 |
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| Bleeding varices |
0.5% |
1.4% |
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Kaplan-Meier estimates of proportions without disease progression (Ddouble-blind treatment & off-treatment follow-up) after 3yrs were 91% on LAM and 79% on placebo (p<0.001).
Kaplan-Meier estimates of proportions with increased Child-Pugh score after 3 yrs was 10% on placebo and 4% on LAM (p=0.023). The lines on the grapg started to separate after 6 months.
Covariate modeling of time to disease showed that the factors to significantly impact the outcome, other than treatment, were baseline Child-Pugh score and baseline Ishak fibrosis score. In both cases, higher scores were associated with a greater frequency of endpoints. Baseline Child-Pugh score >7 was associated with 45% incidence of disease progression on LAM or placebo.
Disease Progression By HBV Genotypes B and C
95% of patients were either genotype B or C
For genotype B patients there was no difference in outcome between LAM (n=118) & placebo (n=53) for all clinical endpoints (15% vs 13%), CP increase (4% vs 4%), and HCC (9% vs 9%).
But there did appear to be a difference for patients with genotype C in outcome based on whether they received LAM (=275) or placebo (n=137): all clinical endpoints 19% for placebo vs 5% for LAM; CP increase, 9% on placebo vs 4% on LAM; HCC, 8% on placebo vs 2% on LAM.
Other measures of efficacy:
HBV-DNA (a result <LLOD of <0.7 MEq/mL on at least one visit: 61% for placebo and 93% for LAM (p<0.001). HBeAg loss with HBeAb (on 2 consecutive occasions at least one month apart): 32% on placebo and 47% on LAM (p<0.01). ALT (a result <ULN on at least one visit): 50% on placebo and 74% on LAM (p<0.001).
Kaplan-Meier estimates of disease progression after 3 years according to YMDD status: 21% on placebo, 13% with YMDD mutation, and 5% with wt.
Incidence of Clinical Endpoints by YMDD Variant HBV Status
Patients with YMDD mutations had increased disease progression compared to patients without mutations: they had less Child-Pugh increase (0.5% vs 6.7%), less HCC 3.6% vs 4.2%), less clinical endpoints (5% vs 11%), and less deaths (0.9% vs 3.8%).
CEP= clinical endpoints
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N |
CP‚ |
HCC |
CEP |
Death |
| LAM |
430 |
3.5% |
4% |
7.9% |
2.3% |
| YMDDwt |
221 |
0.5% |
3.6% |
5% |
0.9% |
| TMDDm |
209 |
6.7% |
4.2% |
11% |
3.8% |
| Placebo |
214 |
8.9% |
7.5% |
18% |
1.9% |
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Treatment was well tolerated. 12% of patients on LAM and 18% on PLB reported serious adverse events during double-blind treatment.
ALT Elevations During Randomized Treatment
≥ 2 x baseline ALT: 40% placebo vs 22% LAM
≥ 3 x baseline ALT: 25% PLB vs 12% LAM
≥ 2 x baseline ALT and ALT >500 U/L: 5% vs 4%
≥ 2 x baseline ALT and >2 x ULN bilirubin and
≥ 2 x baseline bilirubin: 4% vs 2%
CONCLUSIONS
The authors concluded lamivudine reduces disease progression in cirrhotic chronic HBV patients (p=0.001).
Lamivudine may reduce HCC (p=0.047).
Lamivudine is safe and well tolerated in cirrhotic CHB patients for at least 3 yrs.
YMDD mutation emergence (49%) reduced the benefit in delaying disease progression.
Treat early (CP≤6) for optimal benefit |
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