Screening for Hepatocellular Carcinoma and Survival in Patients With Cirrhosis After Hepatitis C Virus Cure

This cohort study assesses whether screening for hepatocellular carcinoma (HCC) is associated with improved survival among individuals with hepatitis C virus (HCV)–associated cirrhosis who achieved HCV cure in the Veteran’s Affairs health system.


Introduction
Hepatitis C virus (HCV) has been the most common cause of cirrhosis and hepatocellular carcinoma (HCC) in the US for decades. 1 Direct-acting antivirals (DAAs) became available in 2014 and revolutionized HCV care, providing an efficacious and well-tolerated cure for HCV for millions of people in the US. 2,3In HCV-associated cirrhosis, early studies 4,5 demonstrated a dramatic decline in HCC rates within 2 to 3 years following HCV treatment with DAAs.[8][9] Multiple observational studies have demonstrated associations of HCC screening, consisting of semiannual imaging and α-fetoprotein measurement, with improved detection of early-stage HCC, receipt of curative treatment, and overall survival. 10However, adherence to screening is poor, with approximately 1 in 4 eligible individuals receiving recommended screening. 11,12Individuals with HCV-associated cirrhosis who have achieved viral cure may be particularly susceptible to lapses in HCC screening due to treatment-induced stabilization of their liver disease. 13However, data on clinical HCC screening practices and outcomes in these patients are sparse.
Screening for HCC in cirrhosis is recommended by all global liver societies, 9,14,15 but its benefits have been controversial. 16Of the 2.5 to 3.5 million individuals affected by HCV in the US, a majority were born between 1945 and 1965. 17This aging population is at risk for comorbid medical conditions that might attenuate the benefit of HCC screening. 18To balance its potential harms, 19,20 it is important to establish the benefits of HCC screening in this population.The objectives of this study were to assess (1) whether HCC screening declines among persons with HCV-associated cirrhosis after HCV cure and (2) whether HCC screening remains associated with improved overall survival in older patients with cirrhosis who received a diagnosis of HCC in the Veterans Affairs (VA) health care system, the largest provider of HCV care in the US. 5

Methods
This is a retrospective cohort study of adults with HCV-associated cirrhosis who achieved DAA-induced viral cure in the VA health care system.This study received institutional review board approval from the VA Connecticut Healthcare System and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.This study was granted institutional review board exemption for informed consent because of the use of deidentified data, in accordance with 45 CFR §46.Development of this cohort has been described previously in detail. 21In brief, cirrhosis was identified using either 1 inpatient or 2 outpatient International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM; 571.2 and

571.5) or International Statistical Classification of Diseases and Related Health Problems, Tenth
Revision (ICD-10; K74.6x and K70.3x) diagnosis codes.Cause of cirrhosis was determined using a validated algorithm. 22Persons with cirrhosis attributed to HCV alone or HCV and alcohol use were considered for inclusion in the analytic cohort.
We identified 19 665 individuals with HCV-associated cirrhosis prescribed a DAA between 2014 and 2021 with a subsequent confirmatory negative HCV RNA polymerase chain reaction test.Individuals with advanced hepatic dysfunction, identified by Child-Turcotte-Pugh (CTP) class C cirrhosis, are unlikely to benefit from HCC treatment 23 and are not recommended for HCC screening unless they are eligible for liver transplantation. 9We therefore excluded 1406 individuals with prevalent HCC, other metastatic cancer (captured using the cirrhosis-specific comorbidity [CirCom] score), or CTP class C cirrhosis before DAA treatment.We excluded individuals with less than 1 year of follow-up

Outcomes
The primary outcomes of this study were incident HCC (measured in the total sample) and survival after diagnosis of HCC.The index date was the date of first DAA prescription that was followed by a negative HCV RNA polymerase chain reaction test 12 weeks after therapy completion.Patients were followed up for incident HCC and death beginning 1 year from the index date.Patients who did not develop HCC or die were censored at their last follow-up or on December 31, 2022, whichever came first.Incident HCC was defined using 1 inpatient or ICD-10-CM, C22.1).These codes have a positive predictive value of 78.2% for confirmed HCC in VA data. 28All-cause mortality and date of death were ascertained using the VA Vital Status Master File.
Cancer stage at HCC diagnosis was defined using the American Joint Commission on Cancer (AJCC) staging manual, which classifies liver cancers by stage groupings from I (least advanced) to IV

JAMA Network Open | Gastroenterology and Hepatology
Screening for HCC and Survival in Patients With Cirrhosis After HCV Cure (most advanced). 29In patients with HCC, multifocal disease and microvascular invasion (characteristics of AJCC stage II disease) are poor prognostic markers. 30Therefore, stage at diagnosis was categorized as early (AJCC stage I) vs all other stages.
The first HCC-directed treatment received (defined as surgical resection, ablation, embolization, radiation, or systemic or supportive therapy) was classified using VA data tables as described previously (eTable 2 in Supplement 1). 28Resection and ablation are potentially curative therapies for HCC.

Statistical Analysis
The analytic sample was described in total and stratified by percentage of time participants were up to date with screening during eligible follow-up (<50% vs Ն50% of eligible follow-up time).Medians with IQRs were calculated for age and compared using Wilcoxon rank-sum tests, and percentages were calculated for categorical variables and compared using χ 2 tests.
The mean percentage of time participants were up to date with screening was calculated by year since HCV cure for up to a maximum of 8 years.Annual cumulative incidence of death, HCC, other metastatic cancer, and CTP class C cirrhosis were calculated for each year of follow-up.

Characteristics of the Study Population
The analytic sample included 16

HCC Screening and Incidence
In the total sample, the mean (SD) percentage of time up to date with screening after HCV cure declined from 53.9% (36.8%) in year 1 to 40.5% (40.5%) in year 4, then increased to a maximum of 64.2% (48.0%) among individuals who remained screening eligible in year 8 (Figure 1).Individuals who were younger at the time of HCV cure spent, on average, less time up to date with screening (eTable 3 in Supplement 1).

Discussion
In this large, well-characterized cohort study of older individuals with HCV-associated cirrhosis, we observed a protective association of screening for HCC with overall survival after HCC diagnosis.
Screening is thought to improve survival through detection of early-stage cancer amenable to curative therapy, and we observed that greater time spent up to date with screening was associated with an increased likelihood of early-stage HCC diagnosis and curative treatment receipt.Lack of recognition of cirrhosis contributes to low HCC screening rates, 11,12 and these findings support efforts to identify cirrhosis among persons with cured HCV and engage appropriate patients in screening.
Screening should be discontinued in patients with limited expected survival due to comorbid illness or CTP class C cirrhosis without liver transplant eligibility.
Few studies examining the outcomes of HCC screening distinguish individuals who have achieved HCV cure from those with chronic HCV, and individuals with treated HCV make up less than 10% of the study population in all but 1 study that makes this distinction. 10One evaluation of HCC screening and survival 32 was performed in a research cohort of individuals with HCV-associated  Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus.
a Annual cumulative incidence of HCC refers to the cumulative incidence over each 1-year period expressed per 100 patient-years of follow-up.
b Calculated using the normal approximation of the binomial distribution.diagnosis of HCC more than 7 months from their last imaging study were characterized as nonadherent and experienced poorer overall survival after HCC diagnosis after adjusting for lead time. 32Our findings in this large cohort of individuals who achieved HCV cure, therefore, add substantially to the evidence evaluating survival outcomes associated with HCC screening in this population.
We also observed an association of percentage of time up to date with screening and improved survival after HCC diagnosis among individuals who were not consistently undergoing screening during eligible follow-up.Although rates of HCC screening in the VA health care system are higher than those in the private sector, 11,12,33 only one-half of our cohort consistently received HCC screening.Thus, our findings are relevant to health care for nonveterans, who typically experience lower rates of HCC screening, and support interventions to improve screening engagement such as patient outreach. 34,35e positive association of screening with overall survival was only observed in individuals who developed HCC between 3 to less than 5 years after HCV cure.As the risk of HCC declines with time after HCV cure, 8 individuals who develop HCC later may have a different risk profile.It is also possible that our study lacked statistical power to detect associations in these strata; only 270 individuals developed HCC 5 or more years after HCV cure and among them, only 53 deaths were observed.
Longer duration of follow-up is needed to evaluate the association of screening with survival more than 5 years after HCV cure and whether discontinuation of screening should be recommended after an adequate interval.

Limitations
Our study has several limitations, most notably its retrospective, observational nature.Despite efforts to address factors that would influence both participation in screening and overall survival at the analysis stage, residual confounding may be present.Individuals who received a diagnosis of HCC had high rates of comorbid disease (46.6% had a CirCom score of 3 + 0 or higher) and less than 5% underwent surgical resection, which are conditions that may have attenuated the observed survival benefit of screening.Female individuals are underrepresented in the VA population, and important sex differences may not be observed in this cohort.Although the use of semiannual α-fetoprotein measurement alongside liver imaging is currently recommended for HCC screening, this was not always the case, so for the sake of consistency over the study period, we evaluated imaging studies alone as representative of HCC screening status.
All evaluations of cancer screening and survival must consider potential biases influencing an observed survival benefit.Most observational studies of HCC screening have compared survival among persons who received a diagnosis of HCC on a screening examination with survival among those who received a diagnosis with symptoms. 10We instead measured the degree to which an individual received screening over the duration of time that they remained eligible, which is a more holistic measurement and does not rely on a single image in time.This approach protects, to a degree, against lead-time bias, which was further assessed by accounting for estimated lead time.

Conclusions
In this cohort study of older adults with cirrhosis and cured HCV, HCC screening was associated with a survival benefit.As the population most impacted by HCV ages, the role of HCC screening after HCV cure requires ongoing evaluation to balance its potential harms and benefits.Our findings suggest that individuals with cirrhosis should be maintained in HCC screening after HCV cure.

Figure
Figure 2. Overall Survival After Hepatocellular Carcinoma (HCC) Diagnosis Among Veterans With Hepatitis C Virus (HCV) Cirrhosis Who Achieved HCV Cure, by Percentage of Time Up to Date With Screening During the 4 Years Preceding HCC Diagnosis

Percentage of Time Participants Were Up to Date With Screening During Eligible Follow-Up
Screening for HCC and Survival in Patients With Cirrhosis After HCV Cure JAMA Network Open.2024;7(7):e2420963. doi:10.1001/jamanetworkopen.2024.20963(Reprinted)July 10, 2024 2/12 Downloaded from jamanetwork.combyguest on 07/14/2024 following initiation of DAA therapy (671 individuals).Patients who received a diagnosis of HCC within 1 year of DAA initiation (679 individuals) were also excluded to avoid capturing prevalent disease.An additional 7 individuals were missing follow-up status.Exposure:

Association of HCC Screening With Mortality Among Those Who Developed HCC Of
the 1622 individuals who developed HCC while eligible for screening and had complete covariable information, those who spent at least 50% of the time up to date with screening during the 4 years preceding HCC diagnosis had improved overall survival after HCC diagnosis (log-rank test of equality over strata P = .002)(Figure2).In multivariable analysis, each 10% increase in the percentage of eligible follow-up spent up to date with screening during the 4 years preceding HCC diagnosis was associated with a 3.2% decrease in the hazard of death after HCC diagnosis (hazard ratio [HR], 0.97; 95% CI, 0.95-0.99)(Table3andfullmodelresults in eTable 4 in Supplement 1).There was a statistically significant interaction between the number of years since HCV cure and percentage of time up to date with screening (χ 2 = 13.6;P=.03).Stratified by year since HCV cure, each 10% increase in the percentage of eligible follow-up spent up to date with screening was associated with a reduction in the hazard of death after HCC diagnosis of 8.0% in individuals who received a diagnosis of HCC 3 to less than 4 years after HCV cure (adjusted HR, 0.92; 95% CI, 0.87-0.98)and13.0%inthosewho received a diagnosis 4 to less than 5 years after HCV cure (adjusted HR, 0.87; 95% CI, 0.79-0.95).There was a no association observed for those who received a diagnosis of HCC more than 5 years after HCV cure (Table3).In sensitivity analyses, results were similar when evaluating screening during the 2 years preceding HCC diagnosis (eTable 5 in Supplement 1) and there was no statistically significant interaction between screening and age at HCC diagnosis (eTable 6 in Supplement 1).Accounting for lead time, overall survival after HCC diagnosis remained higher in those up to date with screening for 50% or more of eligible follow-up (log-rank test of equality over strata P = .04)(eFigureinSupplement 1).In adjusted survival analysis, each 10% increase in time up to date with screening was associated with a 2.0% decrease in the hazard of death after HCC diagnosis (adjusted HR, 0.98; 95% CI, 0.96-1.00)(eTable7 in Supplement 1). of potentially curative treatment (resection or ablation).For every 10% increase in percentage of time spent up to date with screening, individuals with HCC were 10.1% (95% CI, 6.3%-14.0%)morelikely to receive a diagnosis of early-stage disease and 6.8% (95% CI, 2.8%-11.0%)morelikely to receive curative treatment.JAMA Network Open | Gastroenterology and HepatologyScreening for HCC and Survival in Patients With Cirrhosis After HCV Cure JAMA Network Open.2024;7(7):e2420963.doi:10.1001/jamanetworkopen.2024.20963(Reprinted) July 10, 2024 5/12 Downloaded from jamanetwork.comby guest on 07/14/2024

Table 1 .
Characteristics of Participants With HCV Cirrhosis Who Achieved Viral Cure and Participants Who Received a Diagnosis of HCC Screening for HCC and Survival in Patients With Cirrhosis After HCV Cure

Table 1 .
Characteristics of Participants With HCV Cirrhosis Who Achieved Viral Cure and Participants Who Received a Diagnosis of HCC (continued) P values for χ 2 tests (categorical variables) and Wilcoxon rank-sum test (age) comparing individuals up to date with screening for less than 50% vs 50% or greater of the 2-year period preceding HCC diagnosis.Other includes individuals who identified as any other race or ethnicity not otherwise specified or had unknown race and ethnicity.Figure 1. Mean Percentage of Time Eligible Participants Remained Up to Date With Hepatocellular Carcinoma Screening by Year Since Hepatitis C Virus (HCV) Cure a Characteristics at baseline.b Characteristics at diagnosis.c P values for χ 2 tests (categorical variables) and Wilcoxon rank-sum test (age) comparing individuals up to date with screening for less than 50% vs 50% or greater of screening eligible follow-up time.d e

Table 2 .
Annual Cumulative Incidence of HCC Among Those Who Remained Eligible for Screening by Year Since HCV Cure a 2. Overall Survival After Hepatocellular Carcinoma (HCC) Diagnosis Among Veterans With Hepatitis C Virus (HCV) Cirrhosis Who Achieved HCV Cure, by Percentage of Time Up to Date With Screening During the 4 Years Preceding HCC Diagnosis

Table 3 .
Overall Survival After HCC Diagnosis Among Veterans With HCV-Associated Cirrhosis Who Achieved HCV Cure and Developed Incident HCC Model adjusted for age at HCC diagnosis, sex, race and ethnicity, cause of cirrhosis, tobacco use, years since HCV cure, Child-Turcotte-Pugh class at HCC diagnosis, and cirrhosis-specific comorbidity score at HCC diagnosis.
a b Per 10% increase in time participants were up to date with screening.JAMA Network

Open | Gastroenterology and Hepatology Screening
for HCC and Survival in Patients With Cirrhosis After HCV Cure cirrhosis receiving liver imaging every 6 months.A total of 216 individuals developed HCC, but only 42 (19.9%)had achieved HCV cure at least 12 months before HCC diagnosis.Those who received a JAMA Network Open.2024;7(7):e2420963.doi:10.1001/jamanetworkopen.2024.20963(Reprinted) July 10, 2024 8/12 Downloaded from jamanetwork.comby guest on 07/14/2024 Screening for HCC and Survival in Patients With Cirrhosis After HCV Cure Definition of CirCom Categories Based on Comorbidities Present eTable 2. Identification of Surgical and Interventional HCC Treatment Received eTable 3. Distribution of Percent of Time Up-to-Date With Screening During Eligible Follow-Up by Age at Index Date (HCV Cure) eTable 4. Overall Survival After HCC Diagnosis Among Veterans With HCV-Associated Cirrhosis Who Have Achieved HCV Cure and Develop Incident HCC (Full Results) eTable 5. Sensitivity Analysis Evaluating Percent of Time Up-to-Date With Screening During 2 Years Before HCC Diagnosis eTable 6. Proportional Hazard Regression Modeling Overall Survival on Percent of Eligible Follow-Up Up-to-Date With Screening During the 4 Years Preceding HCC Diagnosis Assessing for Interaction Between Age at HCC Diagnosis eFigure.Kaplan-Meier Survival Curve Corrected for Median Lead-Time Estimated for Annual Screening and Stratified by Percent of Time Up-to-Date With Screening During the 4 Years Preceding HCC Diagnosis eTable 7. Sensitivity Analysis Accounting for Median Lead-Time Estimated for Annual Screening eReferences JAMA Network Open.2024;7(7):e2420963.doi:10.1001/jamanetworkopen.2024.20963(Reprinted) July 10, 2024 9/12 Downloaded from jamanetwork.comby guest on 07/14/2024 SUPPLEMENT 1. eTable 1.