The Short-Term Incidence of Hepatocellular Carcinoma Is Not - - PowerPoint PPT Presentation

The Short-Term Incidence of Hepatocellular Carcinoma Is Not Increased After Hepatitis C Treatment with Direct-Acting Antivirals: An ERCHIVES Study

DK Li, YJ Ren, DS Fierer, S Rutledge, OS Shaikh, V Lo Re III, T Simon, A Abou-Samra, RT Chung, AA Butt

Massachusetts General Hospital, Boston VA Pittsburgh Healthcare System, Pittsburgh Icahn School of Medicine, Mt Sinai, New York Perelman School of Medicine, University of Pennsylvania, Philadelphia Hamad Medical Corporation, Doha, Qatar Weill Cornell Medical College, Doha, Qatar & New York

Accepted for Publication in HEPATOLOGY 2018 HKASLD Bi-monthly Scientific Meeting Journal Review James Y.Y. Fung 18th Jan 2018

Introduction

• IFN-induced SVR has been shown to reduce HCC

risk by about 4-fold, regardless of stage of liver disease

• The extrapolation of this benefit to DAAs and the

expectation of greater reduction has not been consistent

• Paradoxical increased risk of HCC in patients

treated with DAA therapy

• 7/16 had been treated initially with

resection and 9/16 with ablation

• Median time from HCC treatment to

DAA was 11.2m (25%-75%: 3.6-23.2)

• Median time from CR to DAA was 1.7

and 1.3 for HCC recurrent patient

• Median time from CR to recurrence

was 3.5 months (1.1-8)

• Recurrence rate is higher than
• bserved in historical non DAA

treated controls

Reig et al. J Hepatol 2016;65:719-726

• Retrospective cohort study
• 344 cirrhotics without HCC at

time of DAAs

• Treated with DAAs and FU for 24

weeks

• SVR 91%
• 59 with HCC history

– 19 resections – 2 resections + RFA – 2 resections + TACE – 18 RFA – 4 RFA + TACE – 6 PEI – 5 TACE – 3 Data not complete

• Median interval between HCC

treatment and DAA 376 days (range, 45-2706)

Conti F et al. J Hepatol 2016;65:727-733 17/59 9/285 26/344 7.6% 3.2% 28.8%

ANRS C022 HEPATHER Cohort ANRS C012 Cirvir Cohort ANRS C023 CUPILT Cohort

13% 21% 1/13 (8%) 31/66 (47%) 2.2%

No increase risk of recurrence of HCC with DAA-treated patients compared with non-treated patients

The ANRS collaborative study group on HCC. J Hepatol 2016

Study Aim

• Whether DAA treatment is associated

with higher rates of incident HCC using a large, well-established national cohort of HCV-infected United States Veterans without a prior diagnosis of HCC

Design & Data Source (I)

• Retrospective cohort study of HCV-infected persons in the

Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database

• All HCV-infected Veterans at any US-wide Dept of Veteran

Affairs medical facilities with anti-HCV+ between 2002 and 2016 were identified

• Demographic, clinical, lab data were obtained from the

National Patient Care Database and the Corporate Data Warehouse

Design & Data Source (II)

• Pharmacy information, including all

prescriptions written, doses, duration, number of pills, number of refills, and date of refills, was retrieved from the Pharmacy Benefits Management database.

• Data merged on established algorithms

Study Participants

• Inclusion criteria

– Anti-HCV+

• Exclusion criteria

– HBV (HBsAg+) or HIV co-infection – Prior to baseline

• Diagnosis of HCC
• Missing HCV RNA or FIB-4 score
• Incomplete data for FIB-4 calculation at least 12 weeks

after baseline

• Missing HCV RNA data for calculation of SVR12

Cohort Groups

• Group A (IFN):

– Received PEG + RBV for ≥28 days – If multiple courses of PR – 1st treatment course used as baseline – Standard IFN excluded

• Group B (DAA)

– Received SOF/SMV±RBV; SOF/LED±RBV; SOF/ DCL±RBV; PRoD±RBV for ≥28 days – Other newer DAAs not included (small numbers)

• Group C

– No HCV treatment for ≥28 days

Baseline Definitions

• For treated groups

– Baseline was the date of HCV treatment initiation

• For untreated groups

– Baseline equal to the duration of HCV infection prior to treatment initiation in the corresponding treated person

• Determining the average time between the first anti-

HCV+ date and treatment initiation date for the treated group

• Adding the same duration to the time between the first

anti-HCV+ date in each untreated person and assigning that date as baseline

Definition of Cirrhosis

• FIB-4 score >3.5

– FIB-4 = (age[years] x AST [IU/L]/(platelet count [platelets x 109/L] x ALT½ [IU/L])

• Lab data obtained at yearly intervals

– FIB-4 score recalculated at each interval

Study Outcomes

• Primary outcome

– Development of incident HCC

• Defined as presence of at least one inpatient or two
• utpatient ICD-9/10 codes for HCC made ≥3 months

after baseline

• Time to development of HCC determined relative from

baseline

• Given that advanced fibrosis is one of the strongest

predictors of HCC development, primary analysis was performed on persons with baseline cirrhosis (FIB-4 >3.5)

Patient Characteristics

Age (yrs) Sex, % male Race, % White Black Hispanic Others Diabetes, % BMI, median Alcohol, % Smoking, % Current Former Never

HCV GT, % 1 2 3 4,5,6 Missing Baseline HCVRNA log PPI use during treatment Statin use prior to baseline FIB-4 baseline, % <1.45 no fibrosis >3.5 cirrhosis 1.45-3.5 Median AFP RBV use, % Treatment, % <8 weeks 8 weeks 12 weeks 24 weeks SVR, % Incident HCC, %

Incidence Rate of HCC by Treatment Group and SVR Status (Entire Cohort)

Incidence Rate of HCC by Treatment Group and SVR Status (Cirrhotics Only)

Treatment Group All cirrhotics IFN DAA regimens Untreated controls SVR12 subgroup IFN DAA regimens Non SVR12 subgroup IFN DAA regimens

Probability of HCC Development in Cirrhotic Person who achieved SVR

Baseline Cohort Characteristics from FIB-4 Sensitivity Analysis (Limiting definition of baseline FIB-4 to within 12 months prior to baseline) Overall 1933 FIB-4 values excluded 209 IFN 82 DAA 1642 untreated

Incidence Rate of HCC in Persons with Cirrhosis, by Treatment Group and SVR Status in FIB-4 Sensitivity Analysis

Baseline Characteristics

• f DAA

Subgroups

Incidence Rate of HCC in Persons with Cirrhosis, by DAA Treatment and SVR Status

Treatment Group Cirrhotics IFN SOF/SMV SOF/LED SVR12 subgroup IFN SOF/SMV SOF/LED Non SVR12 subgroup IFN SOF/SMV SOF/LED

p=0.07

Age, per 10 year increase Male sex Race White (comparator) Black Hispanic Other/Missing Diabetes BMI (per 1 unit increase) Alcohol abuse history Smoking history Non-smoker (comparator) Current smoker Former smoker Missing HCV genotype, % 1 (comparator) 2 3 4,5,6 Missing HCV RNA, per 1 log increase PPI use (baseline onwards) Statin use AFP >20 (vs 20 or below) Treatment regimen Peg/RBV (comparator) Any DAA Attainment of SVR

Predictors for the Development of HCC in Persons with Cirrhosis based on Multivariate, Cox Proportional Hazards Analysis

Predictors for the Development of HCC in Cirrhotics Based on Multivariate Cox Proportional Hazards Analysis in FIB-4 Sensitivity Analysis

Discussion

• DAA-treated persons did have a significantly higher HCC

rate than IFN-treated persons (overall group)

– Higher rate of known risk factors

• Cirrhosis, older age, higher baseline AFP
• Analyzing cirrhotic patients alone showed no difference

in HCC-free survival between DAA and IFN groups

– Lower HCC incidence in sensitivity analysis

• Pre-treatment risk of HCC is the main driver of post-

treatment risk of HCC

Discussion

• Higher prevalence of underlying HCC risks

among DAA patients due to “warehousing”?

• Treatment with earliest DAA regimens may

be surrogate for higher baseline HCC risk

• Failed therapy, cirrhotics
• Persons treated with SIM/SOF had higher

rates of cirrhosis (c/w IFN/later DAAs)

• Previous studies have not provided baseline

data in combination with DAA regimens

Discussion

• In contrast to previous studies, DAA treatment

is not associated with higher risk of HCC compared to IFN treatment when controlling for differences in baseline HCC risk factors

• Achievement of SVR with antiviral regimen is

the most important determinant of a lower HCC risk

Study Limitations

• Relatively short follow-up time in DAA cohort
• Potential for limited generalizability

– Veterans, males, higher smoking & alcohol use

• Retrospective cohort study

– Prospective studies unlikely

• Lack of liver histology for diagnosing cirrhosis
• Lack of info regarding HCC surveillance

practices

• Excluded those with prior HCC

Study Conclusion

• In cirrhotics with chronic HCV infection, there

was no association between HCC incidence rates and DAA treatment compared to IFN

• Insufficient controlling for baseline risks for

HCC and selection bias likely drove previously reported associations between DAA treatment and increased HCC risk