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Severe Hepatitis Flare in Over 6% Stopping HBV Therapy in Taiwan
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AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
Four-year cumulative incidence of severe hepatitis flare stood at 6.58% in a 10,000-person nationwide study in Taiwan after entecavir (ETV) or tenofovir disoproxil fumarate (TDF) stopped [1]. Four-year incidence of death within 6 months of a severe flare measured 0.79%.
Nucleos(t)ide analogs (Nucs) can't cure HBV infection, noted researchers from E-Da Healthcare Group and I-Shou University in Taiwan. Only 2% of a 4769-person international study group taking first-line ETV or TDF for chronic hepatitis B infection cleared hepatitis B surface antigen (HBsAg) from serum in 10 years [2]. Withdrawing NRTIs may promote HBsAg loss, but stopping NRTIs usually leads to viral reactivation-and sometimes in severe life-threatening flares. But the risk of severe flares following NRTI withdrawal remains unclear.
To learn more about flare incidence and risk factors, researchers in Taiwan mounted a nationwide population-based cohort study. In Taiwan people with chronic HBV infection often stop ETV or TDF because national health insurance usually pays for the drugs only for a fixed period. The investigators gathered data from the National Health Insurance Laboratory Databases for previously untreated people starting ETV or TDF who continued treatment for at least 1 year then stopped. The analysis excluded people with severe comorbidities including any malignancy, other viral infections, or alcohol-related disease.
The research team defined severe hepatitis flare as serum alanine aminotransferase (ALT) above 5 times the upper limit of normal (that is, 200 U/L) plus serum bilirubin above 2 mg/dL. They tabulated deaths or liver transplantations within 6 months of severe flare. Follow-up continued until death, liver transplantation, 6 months after retreatment, or December 31, 2018.
Median age stood at 50.9 years in the 10,192 cohort members, 28.3% of whom were women. Rates of notable complications or comorbidities were 10.7% for cirrhosis, 4.6% for hepatic decompensation, 27% for diabetes, 34.6% for hypertension, and 44.9% for abnormal lipids. Median ALT stood at 24 U/L in 7413 people with available data. Two thirds of the group took ETV and one third TDF. Median treatment duration measured 3 years.
During a median 2.15 years of follow-up, 3360 people (35.9%) resumed antiviral therapy. Through 4 years after stopping therapy, 459 people had a severe hepatitis flare for a 4 year cumulative incidence of 6.58% (95% confidence interval [CI] 5.91 to 7.30). Forty-three people died within 6 months of a severe flare and 13 needed a liver transplant for a 4-year death-plus-transplant incidence of 0.79% (95% CI 0.58 to 1.05). Not counting transplants, 4-year mortality came to 0.63%.
Four factors predicted severe flares when Nucs stopped at the following hazard ratios (HR) and 95% CIs:
- Every additional 10 years of age: HR 1.19, 95% CI 1.09 to 1.29, P < 0.0001
- Male sex: HR 1.76, 95% CI 1.41 to 2.22, P < 0.0001
- Diagnosis of cirrhosis: HR 1.84, 95% CI 1.45 to 2.33, P < 0.0001
- History of hepatic decompensation: HR 1.45, 95% CI 1.01 to 2.09, P = 0.044
Factors not associated with flares in this analysis were TDF vs ETV, abnormal lipids, diabetes, and hypertension.
Three variables predicted mortality after a severe flare:
- Every additional 10 years of age: HR 1.70, 95% CI 1.32 to 2.19, P < 0.0001
- Cirrhosis diagnosis: HR 6.12, 95% CI 3.17 to 11.8, P < 0.0001
- Hypertension: HR 2.29, 95% CI 1.09 to 4.82, P < 0.029
The researchers urged informing policymakers-and individuals patients-about risk factors for severe flares and death when people with chronic hepatitis B stop ETV or TDF.
from Jules: in the oral the presenter said "it's difficult to directly confirm casual relationship but robust evidence showed that the majority of severe flares in Asian patients with CHB were the result f HBV replication".
References
1. Hsu YC, Lin YH, Lee TY, et al. Severe hepatitis flare and related mortality after discontinuation of oral antiviral treatment in patients with chronic hepatitis B: a population-based study. AASLD, The Liver Meeting, November 12-15, 2021. Parallel session 1: Advances With Approved HBV Therapies.
2. Hsu YC, Yeh ML, Wong GL, et al. Incidences and determinants of functional cure during entecavir or tenofovir disoproxil fumarate for chronic hepatitis B. J Infect Dis. 2021 May
17:jiab241. doi: 10.1093/infdis/jiab241. https://pubmed.ncbi.nlm.nih.gov/33999179/
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