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  The Liver Meeting
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November 13 - 16 - 2021
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HCC Risk Factors After HCV Cure Differ
With vs Without Cirrhosis and Over Time

  AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
Risk factors for development of hepatocellular carcinoma (HCC) after virologic HCV cure with direct-acting antivirals (DAAs) differed between people who initially had cirrhosis and those who did not, according to a 98,612-person US veteran analysis [1]. Because risk factors could change from 12 to 24 months after HCV cure, a team parsing US Veterans Affairs data believes risk estimates can be improved by repeating assessments 2 years after HCV cure.
Researchers at the Michael E. DeBakey VA Medical Center in Houston and collaborators at other centers noted that HCC risk persists after virologic cure of HCV infection with DAAs, but little research has examined how risk factors may change with time since HCV cure or whether HCC risk differs between people with or without baseline cirrhosis.
To address these questions, the investigators tapped data in the National Veterans Administration Corporate Data Warehouse and the Central Cancer Registry. The study included people with HCV who attained sustained virologic response (SVR) with DAAs between January 2014 and December 2018. Participants had to be at least 18 years old and could be in care at any of the 130 VA facilities across the United States. The researchers identified incident HCC through the Central Cancer Registry or by finding two or more ICD-9 or ICD-10 codes indicating HCC. They recorded variables of interest at baseline and 1 and 2 years after SVR.
The analysis focused on 98,612 people with a virologic HCV cure, 2298 of whom got an HCC diagnosis after that cure during an average 3.1 years of follow-up. While 31,543 people had cirrhosis, 67,069 did not.
People with or without cirrhosis did not differ substantially in age (average 61.6 years overall) or proportions of men (96.4% overall), whites (51.2%), blacks (38.5%), or Hispanics (3.5%). People with cirrhosis had higher bilirubin and higher albumin, but similar creatinine and hemoglobin. The cirrhosis group had a higher diabetes prevalence (44.1% vs 33.8%) but similar rates of hypertension (87.1% and 81.8%), abnormal lipids (52.1% and 51.1%), and current smoking (45.0% and 50.5%).
In people without cirrhosis, annual HCC incidence measured 0.21% 1 year after HCV cure and 0.27% 2 years after cure. Annual HCC incidence was more than 7-fold higher in people with cirrhosis-1.6% 1 year after HCV cure and 1.9% 2 years after cure.
In people virologically cured of HCV infection and with cirrhosis, risk factors for HCC included demographic variables like sex and race, viral risk factors like HCV genotype 3, and cirrhosis-related factors like longer cirrhosis duration, varices, higher bilirubin, and lower albumin, as indicated by the following hazard ratios (HR) (and 95% confidence intervals):
Lower HCC risk in women than men:
- Women vs men at baseline: HR 0.55 (0.38-0.79, P = 0.0013)
- At 12 months: HR 0.60 (0.40-0.90, P = 0.0139)
- At 24 months: HR 0.45 (0.23-0.82, P = 0.095)
Lower HCC risk in blacks than whites
- Blacks vs whites at baseline: HR 0.80 (0.71-0.90, P = 0.0002)
- At 12 months: HR 0.86 (0.74-0.99, P= 0.0322)
- At 24 months: not significant
Higher HCC risk with HCV genotype 3 vs 1a
- HCV genotype 3 vs 1a at baseline: HR 1.45 (1.22-1.73, P < 0.0001)
- At 12 months: HR 1.47 (1.19-1.81, P = 0.0004)
- At 24 months: Not significant
Higher HCC risk with varices
- With vs without varices at baseline: HR 1.62 (1.45-1.81, P < 0.0001)
- At 12 months: HR 1.58 (1.38-1.80, P < 0.0001)
- At 24 months: HR 1.75 (1.48-2.06, P < 0.0001)
For people with virologically cured HCV infection without cirrhosis, key predictors were metabolic conditions like diabetes and hypertension and increasing FIB-4 indicating worsening fibrosis, as indicated by the following HR (and 95% confidence intervals):
Higher HCC risk with diabetes
- With vs without diabetes at baseline: HR 1.42 (1.19-1.70, P = 0.0001)
- At 12 months: HR 1.42 (1.16-1.75, P = 0.0008)
- At 24 months: HR 1.42 (1.09-1.84, P = 0.0085)
Higher HCC risk with hypertension
- With vs without hypertension at baseline: HR 2.06 (1.52-2.79, P < 0.0001)
- At 12 months: HR 2.13 (1.47-3.07, P < 0.0001)
- At 24 months: HR 1.81 (1.13-2.91, P = 0.0143)
Higher HCC risk with FIB-4 increase from low to high from baseline to 12 or 24 months
- At 12 months: HR 2.36 (1.46-3.79, P = 0.0005)
- At 24 months: HR 2.04 (1.01 to 4.10, P = 0.0455)
In the group with baseline cirrhosis, nonsmokers had a significantly lower risk of HCC than current smokers at baseline (HR 0.79, 95% CI 0.67-0.93, P = 0.005) and 12 months after HCV cure (HR 0.77, 95% CI 0.65-0.92, P = 0.0038) but not 24 months after HCV cure. Among people without baseline cirrhosis, nonsmokers did not have a significantly lower risk of HCC at baseline, 12 months after cure, or 24 months after cure when compared with current smokers.
Summing up, the researchers stressed that in people with virologically cured HCV infection, HCC risk factors differed between people with and without baseline cirrhosis. For those with cirrhosis, HCC risk factors mainly involved disease severity, while in people without cirrhosis, metabolic traits held sway as dominant risk factors.
Because risk could change from 12 months to 24 months after cure, the investigators argued that "risk assessment based on repeat measurements at 2 years is practical and can improve risk stratification in patients with virologically cured HCV, regardless of their cirrhosis status at baseline."
1. Kramer JR, Cao Y, Li L, et al. Longitudinal associations between risk factors and subsequent risk of hepatocellular cancer in patients with hepatitis C virus infection and virological cure. AASLD, The Liver Meeting, November 12-15, 2021. Abstract 903.