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Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study
Gastroenterology 2019;-:1–10
Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study Q5
Amit G. Singal,1 Nicole E. Rich,1 Neil Mehta,2 Andrea Branch,3 Anjana Pillai,4 Maarouf Hoteit,5 Michael Volk,6 Mobolaji Odewole,1 Steven Scaglione,7,8 Jennifer Guy,9 Adnan Said,10 Jordan J. Feld,11 Binu V. John,12 Catherine Frenette,13 Parvez Mantry,14 Amol S. Rangnekar,15 Omobonike Oloruntoba,16 Michael Leise,17 Janice H. Jou,18 Kalyan Ram Bhamidimarri,19 Laura Kulik,20 Tram Tran,21 Hrishikesh Samant,22 Renumathy Dhanasekaran,23 Andres Duarte-Rojo,24 Reena Salgia,25 Sheila Eswaran,26 Prasun Jalal,27 Avegail Flores,28 Sanjaya K. Satapathy,29 Robert Wong,30 Annsa Huang,2 Suresh Misra,3 Myron Schwartz,3 Robert Mitrani,5 Sasank Nakka,6 Wassim Noureddine,6 Chanda Ho,9 Venkata R. Konjeti,12 Alexander Dao,15 Kevin Nelson,17 Kelly Delarosa,21 Usman Rahim,23 Meher Mavuram,22 Jesse J. Xie,31 Caitlin C. Murphy,1,§ and Neehar D. Parikh32,§ 1
Q1
Division of Digestive and Liver Disease, UT Southwestern Medical Center; 2Division of Gastroenterology, University of California San Francisco; 3Department of Medicine, Icahn School of Medicine at Mount Sinai; 4Division of Gastroenterology, Hepatology and Nutrition, University of Chicago; 5Division of Gastroenterology and Hepatology, University of Pennsylvania; 6 Transplantation Institute and Division of Gastroenterology, Loma Linda University Health; 7Division of Hepatology, Loyola University Medical Center and 8Edward Hines Veterans Affairs; 9Department of Transplantation, California Pacific Medical Center; 10Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine; 11Toronto Center for Liver Disease, Toronto General Hospital; 12Division of Gastroenterology and Hepatology, McGuire VA Medical Center; 13Division of Organ Transplantation, Scripps Green Hospital; 14Liver Institute at Methodist Dallas; 15Division of Gastroenterology, Georgetown University Hospital; 16Division of Gastroenterology and Hepatology, Duke University Health Center; 17Division of Gastroenterology and Hepatology, Mayo Clinic; 18Division of Gastroenterology and Hepatology, Oregon Health and Science University; 19Division of Hepatology, University of Miami Miller School or Medicine; 20Division of Hepatology, Northwestern University; 21Liver Disease and Transplant Center, Cedars-Sinai Medical Center; 22Division of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center; 23Division of Gastroenterology and Hepatology, Stanford University; 24Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences; 25Division of Gastroenterology and Hepatology, Henry Ford Hospital; 26Division of Gastroenterology, Rush Medical College; 27Division of Abdominal Transplantation, Baylor College of Medicine; 28Division of Gastroenterology, Washington University School of Medicine; 29Division of Transplant Surgery, University of Tennessee Health Science Center; 30Division of Gastroenterology and Hepatology, Alameda Health System; 31Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences; 32Division of Gastroenterology and Hepatology, University of Michigan
Direct-Acting Antiviral Therapy is not Associated with HCC Recurrence: A Multicenter North American Cohort Study Conflicting data on whether direct acting antiviral hepatitis C treatment impacts the risk of hepatocellular carcinoma recurrence
Methods: 31 centers in North America including patients with HCV-related HCC with complete radiographic response
Results: 304 Treated with DAAs 489 Treatment naïve HCV DAA therapy has no impact on: HCV related HCC
DAA therapy for HCV
HCC with complete response p
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Recurrent HCC
• Overall HCC recurrence (aHR: 0.90 95% CI: 0.90-1.17) • Early HCC recurrence (aHR: 0.96 95% CI: 0.69-1.33)
Aim: Do DAAs impact the risk of HCC recurrence? Singal AG et al. Gastroenterology. 2019
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BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70–1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70–1.34) after we adjusted for study site, age, sex, Child-Pugh score, a-fetoprotein level, tumor burden, and HCC treatment modality. In DAAtreated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P ¼ .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients. Keywords: Hepatitis C Virus; Liver Cancer; Recurrence; DirectActing Antiviral.
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hronic hepatitis C virus (HCV) infection affects more than 3.2 million persons in the United States, where it is the most common cause of hepatocellular carcinoma (HCC).1 Highly effective direct-acting antiviral (DAA) therapies against HCV infection have the potential to decrease HCV-related HCC incidence2,3; however, suboptimal rates of HCV screening and treatment make this unlikely in the near future. It is estimated that 50% of patients with HCV are currently unaware of their infection and more than one fourth of patients with HCC have unrecognized HCV at time of tumor diagnosis.4 Therefore, the HCV-related HCC incidence could continue to increase over the next decade, if not longer. Patients diagnosed with HCC at an early stage are eligible for curative treatments including surgical resection or local ablative therapies; however, unlike liver transplantation, these therapies are limited by high recurrence.5,6
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WHAT YOU NEED TO KNOW BACKGROUND There are conflicting data concerning hepatocellular carcinoma (HCC) recurrence risk and aggressiveness in patients treated for hepatitis C with direct-acting antiviral (DAA) therapy. NEW FINDINGS In a large multicenter North American cohort, DAA therapy was not associated with an increased risk of HCC recurrence when compared to patients who were not treated for hepatitis C. HCC recurrence patterns, including treatment response, were also similar in DAAtreated and untreated patients. LIMITATIONS This study was limited by possible ascertainment bias for hepatocellular carcinoma recurrence, lack of centralized radiology review, and potential for residual confounding. IMPACT Treatment of hepatitis C with direct-acting antiviral therapy appears to be safe in patients who have achieved complete response to hepatocellular carcinoma therapy.
Historically, sustained viral response (SVR) using interferon (IFN)-based therapy for HCV was associated with significant decreases in HCC recurrence after curative treatment.7 However, IFN-based therapy elicited an SVR in only approximately 40%–50% of treated patients and could not be tolerated by many patients with cirrhosis. It is unclear whether DAA therapies have similar chemopreventive benefits for decreasing HCC recurrence in patients who achieved complete response (CR) to prior HCC-directed treatment. In fact, some observational data suggest potential increased risk of HCC recurrence after DAA therapy.8,9 One study reported high early tumor recurrence risk in patients with HCC who received DAA therapy.9 Of 58 patients with a CR, HCC recurred in 27% at a median follow-up of 5.7 months. However, the small cohort, lack of an untreated control arm, and short median duration of follow-up limited any definitive conclusions about harms related to HCV therapy, including which patients were at highest risk for early recurrence.10 Larger multicenter efforts, particularly those with comparator groups, are crucial to better understand the potential benefits and harms of HCV therapy with DAAs in patients with HCC. The aim of the present multicenter study was to compare overall and early HCC recurrence between DAA-treated and untreated
§
Authors share co-senior authorship.
Abbreviations used in this paper: AFP, a-fetoprotein; CI, confidence interval; CR, complete response; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IFN, interferon; IQR, interquartile range; SVR, sustained viral response. © 2019 by the AGA Institute 0016-5085/$36.00 https://doi.org/10.1053/j.gastro.2019.01.027
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patients in a large cohort of patients with CR to prior HCCdirected therapy.
Methods Study Design and Patient Population We conducted a multicenter retrospective cohort study of adult patients with HCV-related HCC who achieved HCC CR from January 2013 through December 2017. Patients were recruited from 31 health systems throughout the United States and Canada. HCC diagnosis was based on American Association for the Study of Liver Diseases criteria (ie, histologic confirmation or lesions >1 cm with characteristic appearance at imaging [arterial enhancement and delayed washout]).11 Patients were required to have liver-localized tumor burden at time of presentation, and patients with extrahepatic disease (lymph node involvement or metastatic spread) were excluded. We included patients who achieved HCC CR by surgical resection, local ablative therapies, transarterial chemoembolization or bland embolization, or transarterial radioembolization or stereotactic body radiation therapy; however, patients with CR after liver transplantation or systemic therapy were excluded. CR to HCC treatment was defined by modified Response Evaluation Criteria in Solid Tumors criteria (ie, disappearance of arterial enhancement from all HCC lesions on contrastenhanced cross-sectional imaging). We excluded patients with unknown HCC response (eg, lack of contrast-enhanced imaging after HCC treatment) and patients with HCC recurrence within 30 days of CR. Patients were categorized into DAA-treatment and untreated groups. The DAA-treatment group included patients who received DAA therapy, independent of SVR12, after HCC CR; the untreated group included those who did not receive DAA therapy. We excluded patients who received IFN-based therapy during the study period, completed DAA therapy before HCC CR, or completed DAA therapy after suspected HCC recurrence. The study was approved by the institutional review boards at each study site.
Data Collection We used a standardized data collection template to obtain demographic and clinical variables at time of HCC presentation from electronic medical records at each site for all patients, including age, sex, race–ethnicity, body mass index, presence of hepatitis B and human immunodeficiency viral coinfection, platelet count, aspartate aminotransferase, alanine aminotransferase, HCV viral load, HCV genotype, Eastern Cooperative Oncology Group performance status, and a-fetoprotein (AFP). Degree of liver dysfunction was assessed by Child-Pugh and Model for End-Stage Liver Disease scores. Tumor burden, as determined by interpretation of imaging by local radiologists at each site, was categorized as very early stage (single tumor <2 cm), early stage (single tumor <5 cm or 2–3 tumors each with <3 cm in maximum diameter), or intermediate stage (beyond early stage but without extrahepatic spread). We recorded the number of HCC-directed treatments needed to achieve CR and type of treatment leading to HCC CR. For DAA-treated patients, we collected DAA treatment regimen, time from HCC CR to DAA initiation, HCV viral load at weeks 4 and 12 of treatment, and DAA treatment outcome (ie, SVR).
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We assessed time from initial HCC CR to last imaging with confirmed CR and first imaging with HCC recurrence. For patients with HCC recurrence, we collected data on degree of liver dysfunction, type of recurrence (local vs new intrahepatic lesion), tumor burden, AFP, and type of HCC-directed treatment.
Statistical Analysis We compared treatment groups (DAA-treated and untreated) using c2 and Student t tests for categorical and continuous variables, respectively. We characterized time to recurrence from time of HCC CR. Patients in the 2 groups were followed from CR until recurrence, death, liver transplantation, or last clinic visit. Patients who initiated DAA therapy after HCC recurrence or liver transplantation were considered untreated. We estimated crude and adjusted hazard ratios (HRs) comparing patients treated with DAAs with those who were not treated with DAAs using a Cox proportional hazards regression model, with DAA therapy as a time-varying exposure. In brief, this method assigns follow-up time for patients before DAA initiation as unexposed time and time after DAA initiation as exposed time. We present crude and confounder-adjusted HRs (adjusted for study site, age, sex, Child-Pugh class, HCC tumor stage, AFP level, and type of HCC treatment). Confounders were selected a priori given their known association with DAA therapy receipt and HCC recurrence risk. We also estimated risk of early HCC recurrence by truncating follow-up time at 365 days of CR. In this analysis, patients who initiated DAA >365 days after achieving HCC CR were included in the untreated group. To account for the possibility that DAAs have a time-varying treatment effect, we compared the untreated group with patients who initiated DAA 6 months after CR and those in whom DAA therapy was delayed >6 months after CR. We also conducted secondary analyses stratified by tumor burden (within vs beyond Milan criteria), treatment leading to HCC CR (resection vs ablation vs transarterial chemoembolization and stereotactic body radiation therapy), and SVR status. To assess the robustness of the time-varying exposure approach, we performed a sensitivity analysis using a landmark approach to compare risk of HCC recurrence between DAAtreated and untreated groups. This approach avoids immortal time bias by synchronizing the start of follow-up for the treated and untreated groups.12,13 We started follow-up at 90, 120, and 180 days after CR to investigate the impact of landmark choice on the outcome. Patients who had HCC recurrence, died, underwent liver transplantation, or had a last clinic visit before the landmark point were excluded. Patients who initiated DAA therapy before the landmark were categorized as treated with DAA and those initiating DAA therapy after the landmark were included in the untreated group. To minimize potential for confounding, we computed a propensity score for each patient predicting the probability of initiating DAA conditional on patient characteristics (at CR) using multivariable logistic regression. The propensity score model included factors associated with initiating DAA therapy and/or recurrence, including study site, age, sex, Child-Pugh class, baseline tumor burden, AFP level, and treatment leading to CR. We estimated crude and adjusted (by inverse probability of treatment weights) HRs comparing patients treated with DAAs and those who were untreated using a Cox proportional hazards regression model.
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All tests were 2-sided and performed at the 5% significance level. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).
Results Patient Characteristics
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Selection of the study population is illustrated in Figure 1. We initially identified 1075 patients with HCVinfected HCC who achieved CR to HCC-directed therapy from January 2013 through December 2017. After excluding 225 patients who initiated DAA therapy before CR to HCC therapy, 850 patients remained. We excluded an additional 45 patients with DAA initiation and 12 patients with HCC recurrence within 30 days of HCC CR. A total of 793 patients were included in the final analysis, of whom 304 had been treated with DAA therapy and 489 were untreated. Patient demographics are presented in Table 1. Median age was 61.6 years. Most patients were men and nonHispanic white. At time of HCC diagnosis, nearly three fourths of patients had unifocal HCC and more than 80% were within Milan criteria. More than 50% of patients achieved HCC CR from locoregional therapy such as transarterial chemoembolization, whereas one third achieved CR from local ablation and 14% from surgical resection. Median time from HCC diagnosis to treatment was 2.7 months (interquartile range [IQR] 1.4–5.6) and median time from treatment to HCC CR confirmation was 1.6 months (IQR 1.1– 3.2). DAA-treated patients were older, had more preserved liver function (larger proportion with compensated cirrhosis and less portal hypertension), and were more likely to have achieved HCC CR by resection than untreated patients; however, the 2 groups had similar tumor burden at presentation, with no significant difference in the proportion presenting within Milan criteria. A larger proportion of DAA-untreated patients were listed and underwent liver transplantation than DAA-treated patients (29.4% vs 18.8%; P ¼ .001).
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Median time from HCC CR to DAA initiation was 5.8 months (IQR 3.0–11.5), with 25.0% treated within 3 months, 26.3% within 3–6 months, 24.7% treated within 6– 12 months, 18.4% treated within 12–24 months, and 5.6% treated more than 24 months after HCC CR confirmation. Most patients had genotype 1 HCV infection, and the most common DAA regimens were sofosbuvir and ledipasvir with or without ribavirin and sofosbuvir with ribavirin. SVR12 was documented in 81.8% of DAA-treated patients, with no significant differences by HCV genotype (P ¼ .16), DAA regimen (P ¼ .11), or time to DAA treatment after HCC CR (P ¼ .44).
Time to HCC Recurrence Over a median follow-up of 10.4 months (IQR 5.3–20.8), there were 416 recurrences, including 128 after initiation of DAA treatment and 288 in untreated patients. DAA therapy, when analyzed as a binary exposure, was associated with lower risk of HCC recurrence (HR 0.32, 95% confidence interval [CI] 0.25–0.41) after adjusting for study site, age, sex, Child-Pugh score, AFP level, initial tumor burden, and HCC therapy. The median time to recurrence in DAA-treated patients was 13.2 months (IQR 8.4–21.8) compared with 6.0 months (IQR 3.6–10.6) for untreated patients. However, after accounting for time-varying exposure, DAA therapy was no longer associated with HCC recurrence in crude (HR 0.79, 95% CI 0.63–1.00) and adjusted (HR 0.90, 95% CI 0.70–1.16) analyses. The propensity score model showed similar results, with DAA therapy not associated with HCC recurrence risk (HR 0.91, 95% CI 0.69–1.19). In sensitivity analyses using a landmark approach to minimize immortal time bias, DAA therapy was not significantly associated with increased or decreased risk of HCC recurrence. These results were consistent whether follow-up was started at 90 days (HR 0.92, 95% CI 0.60–1.41), 120 days (HR 0.99, 95% CI 0.66–1.48), or 180 days (HR 0.98, 95% CI 0.69–1.40) from HCC CR (Figure 2).
Figure 1. Study cohort inclusion and exclusion diagram.
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Table 1.Patient Characteristics Variablea
DAA-treated (n ¼ 304)
DAA-untreated (n ¼ 489)
Age at time of complete response (y) Sex (% men) Race–ethnicity Non-Hispanic white Hispanic white Black Other Missing HCC nodules at diagnosis 1 2 3 4 Maximum HCC diameter (cm) at diagnosis HCC within Milan criteria at diagnosis AFP at time of HCC diagnosis (ng/mL) Treatment leading to CR Resection Local ablation TACE TARE, SBRT, other Missing HCC therapies required to achieve CR 1 2 3 Missing Child-Pugh class at CR A B C Presence of ascites Presence of hepatic encephalopathy Platelet count at CR Bilirubin at CR (mg/dL) HCV genotype 1 2 3 4–6 Missing Viral coinfection Hepatitis B virus HIV DAA regimenb Sofosbuvir þ ledipasvir Sofosbuvir Simeprevir þ sofosbuvir Sofosbuvir þ velpatasvir Daclatasvir þ sofosbuvir Ombitasvir þ partiprevir þ ritonavir þ dasabuvir Elbasavir ¼ grazoprevir Other DAA regimen duration <12 wk 12 wk >12–<24 wk 24 wk >24 wk Missing
62.4 (59.0–66.5) 214 (70.4)
61.3 (57.4–65.2) 373 (76.3)
156 44 59 13 32
(51.3) (14.5) (19.4) (4.3) (10.5)
191 82 103 24 89
(39.1) (16.8) (21.1) (4.9) (18.2)
231 56 12 5 2.4 246 18.5
(76.0) (18.4) (4.0) (1.6) (1.7–3.5) (81.7) (7.6–64.7)
343 99 32 15 2.5 400 18.4
(70.1) (20.2) (6.5) (3.1) (2.0–3.6) (82.3) (7.7–67.3)
64 107 107 26 0
(21.1) (35.2) (35.2) (8.5) (0)
47 157 253 30 2
(9.6) (32.1) (51.7) (6.1) (0.4)
189 68 37 10
(62.1) (22.4) (12.2) (3.3)
243 125 86 35
(49.7) (25.6) (17.6) (7.1)
191 96 17 75 42 112 1.0
(62.8) (31.6) (5.6) (24.7) (13.8) (76–163) (0.6–1.7)
244 188 57 177 106 89 1.2
(49.9) (38.4) (11.7) (36.2) (21.6) (60–135) (0.7–2.0)
240 26 31 5 2
(78.9) (8.6) (10.2) (1.6) (0.7)
331 17 70 17 54
(67.7) (3.5) (14.3) (3.5) (11.0)
P value .03 .07 .005
.17
.85 .84 .66 <.001
.04
<.001
.001 .006 <.001 .32 <.001
.10 8 (2.6) 7 (2.3)
5 (1.0) 8 (1.6)
188 49 27 15 10 6 3 6
(61.8) (16.2) (8.9) (4.9) (3.3) (2.0) (1.0) (1.9)
N/A
10 169 18 97 6 4
(3.3) (55.6) (5.9) (31.9) (2.0) (1.3)
N/A
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Table 1. Continued Variablea Time from HCC CR to DAA <3 mo >3–6 mo >6–12 mo >12–24 mo >24 mo
DAA-treated (n ¼ 304) 76 80 75 56 17
DAA-untreated (n ¼ 489)
(25.0) (26.3) (24.7) (18.4) (5.6)
P value
N/A
HIV, human immunodeficiency virus; N/A, not applicable; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization. a Continuous data are presented as median (IQR). b All DAA regimens are with or without ribavirin.
Results were consistent across all subgroup analyses, stratified by tumor burden and treatment type leading to CR (Supplemental Table 1). Although DAA therapy was associated with lower recurrence risk in the subgroup of patients who achieved CR after resection, this difference did not reach statistical significance (HR 0.61, 95% CI 0.28–1.32). We also found no difference in the association between DAA therapy and HCC recurrence risk by SVR status, although the number of patients who did not achieve SVR was small, or timing of DAA therapy in relation to CR (Supplemental Table 1). In a sensitivity analysis excluding 27 patients with prior HCC recurrence, DAA therapy continued to have no significant association with HCC recurrence (HR 0.91, 95% CI 0.70–1.18). Compared with untreated patients, DAA therapy was not associated with differential recurrence risk in patients who initiated DAA therapy within 6 months of CR (HR 0.90, 95% CI 0.67–1.21) or those who delayed DAA >6 months after CR (HR 0.90, 95% CI 0.64–1.27). The
proportions of patients with HCC recurrence were 44.0% for those initiating DAA within 3 months of HCC CR, 50.0% for those initiating DAA 4–6 months after HCC CR, and 36.9% for those initiating DAA after 6 months.
Time to Early HCC Recurrence There were 52 patients (17.1%) in the DAA-treated group and 227 (46.4%) in the untreated group who developed early recurrence within 365 days of HCC CR. DAA therapy, when analyzed as a binary exposure, was associated with lower risk of early HCC recurrence (HR 0.44, 95% CI 0.32–0.61) after adjusting for study site, age, sex, ChildPugh score, AFP level, initial tumor burden, and HCC therapy. However, accounting for time-varying exposure, there was no significant association between DAA therapy and early HCC recurrence in crude (HR 0.81, 95% CI 0.60–1.10) or adjusted (HR 0.96, 95% CI 0.70–1.34) analyses. The propensity score model showed similar results, with DAA
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Figure 2. Time to HCC recurrence, stratified by receipt of DAA HCV therapy, and landmark analysis of 90 days after HCC CR.
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Q3
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721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
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DAA Therapy and HCC Recurrence
therapy not associated with increased HCC recurrence (HR 0.96, 95% CI 0.67–1.38). Results of the time-varying exposure analysis were consistent in subgroup analyses, stratified by tumor burden and treatment leading to CR (Supplemental Table 1). Similarly, there was no difference in the association between DAA therapy and early HCC recurrence risk by SVR status. Compared with untreated patients, risk of early HCC recurrence appeared to potentially differ by timing of DAA therapy. DAA initiation within 6 months of HCC CR was not associated with early HCC recurrence (HR 1.05, 95% CI 0.74–1.48). Although patients who delayed DAA therapy >6 months after HCC CR had lower risk of early HCC recurrence (HR 0.56, 95% CI 0.22–1.38), this did not reach statistical significance likely related to the small sample.
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recurrence presented as local recurrence, new intrahepatic lesion, and extrahepatic disease in 28.9%, 55.5%, and 7.8% of DAA-treated patients versus 38.2%, 50.3%, and 5.9% of untreated patients, respectively. In DAA-treated and untreated groups, most recurrences were detected at an early stage (74.2 vs 78.8% within Milan criteria, respectively; 70.3% vs 67.7% at Barcelona Clinic Liver Cancer stage 0/A, respectively). A larger proportion of DAA-treated patients received potentially curative therapy (transplantation, resection, or ablation) for HCC recurrence compared with untreated patients (32.0% vs 24.6%), although this did not reach statistical significance (P ¼ .15). Similarly, there was no significant difference in the proportion that achieved CR or partial response to treatment of HCC recurrence.
Discussion Recurrence Patterns and Treatment Response Recurrence patterns did not significantly differ between DAA-treated and untreated patients (Table 2). HCC
To the best of our knowledge, this study represents the largest study to date comparing HCC recurrence risk between DAA-treated patients and a contemporary group of
Table 2.HCC Recurrence Patterns and Treatment Variablea Type of recurrence Local Distant Missing HCC nodules 1 2 3 4 Infiltrative Missing Maximum tumor diameter (cm) Vascular invasion Distant metastases HCC within Milan criteria BCLC tumor stage 0/A B C D Missing Treatment of HCC recurrence Liver transplantation Surgical resection Local ablation TACE, TARE, SBRT Systemic therapy Best supportive care Missing Response to HCC treatment CR Partial response Stable disease Progressive disease Unknown or missing
DAA-treated (n ¼ 128)
DAA-untreated (n ¼ 288)
P value .33
37 (28.9) 81 (63.3) 10 (7.8)
110 (38.2) 162 (55.3) 16 (5.5)
77 30 8 8 4 1 1.8 7 11 95
(60.1) (23.4) (6.3) (6.3) (3.1) (0.8) (1.2–2.7) (5.4) (8.6) (74.2)
173 61 20 15 15 5 1.6 10 17 227
(60.1) (21.2) (6.9) (5.2) (5.2) (1.4) (1.2–2.5) (3.5) (5.9) (78.8)
90 11 16 11 0
(70.3) (8.6) (12.5) (8.6) (0)
195 17 28 46 2
(67.7) (5.9) (9.7) (16.0) (0.7)
10 2 29 55 8 21 3
(7.8) (1.6) (22.6) (43.0) (6.3) (16.4) (2.3)
18 11 42 153 11 47 6
(6.2) (3.8) (14.6) (53.1) (3.9) (16.3) (2.1)
43 15 15 17 38
(33.6) (11.7) (11.7) (13.3) (29.7)
91 27 40 57 73
(31.6) (9.4) (13.9) (19.8) (25.3)
.87
.29 .34 .28 .23 .16
.15
.31
BCLC, Barcelona Clinic Liver Cancer; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization. a Continuous data are presented as median (IQR).
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CLINICAL LIVER
-
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840
8
Q2
CLINICAL LIVER
841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900
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untreated patients. We found DAA therapy was not associated with overall or early HCC recurrence after CR. Similarly, we did not observe any differences in patterns or aggressiveness of HCC recurrence between DAA-treated and untreated patients. A prior meta-analysis of relevant literature found no association between DAA therapy and de novo or recurrent HCC.14 Similarly, an updated meta-analysis identified 9 studies that compared HCC recurrence in DAA-treated patients (n ¼ 947) with IFN-treated (n ¼ 210) and/or untreated (n ¼ 641) patients.10 Among studies reporting relative risk of recurrence, DAA-treated patients had a lower pooled recurrence risk than untreated patients (odds ratio 0.55, 95% CI 0.25–0.85); however, most prior studies analyzed DAA treatment as a fixed binary exposure, which ignores the time dependency of DAA exposure and potentially leads to inaccurate HR estimates.15 Our results highlight the importance of analyzing DAA therapy as a time-varying exposure, because we found significant differences compared with the binary exposure analysis. There is a tendency for patients with early HCC recurrence to be artifactual members of the untreated group simply because early recurrence decreases the time available to start DAAs before recurrence. Because cohort studies also can be limited by immortal time bias, in which HCC recurrence could not occur before DAA exposure, we also conducted landmark analyses anchored at 3 different time points. Although we found decreased risk of HCC recurrence in DAA-treated patients in binary analyses, this difference was mitigated in time-varying analyses. Although we found no association between DAA therapy and risk of HCC recurrence, we found the risk of early recurrence can differ by timing of DAA therapy. Prior studies have reported an association between HCC recurrence and timing of DAA therapy initiation, with later initiation associated with lower HCC recurrence risk16–18; however, the mechanism underlying this association remains unclear. It has been hypothesized that early DAA therapy and rapid viral clearance might quickly blunt hepatic inflammation, resulting in an “immune break” that allows unchecked growth of microscopic tumor clones19; however, this has yet to be proved. Alternatively, delaying DAA therapy might allow more time for repeat imaging to verify HCC CR and minimize the chance of misclassification bias. This is important because more than 50% of subcentimeter lesions and more than 25% of 1- to 2-cm lesions can be missed by 1-time computed tomography or magnetic resonance imaging.20 Therefore, many “early HCC recurrences” might actually be pre-existing HCC cases that were preclinical at imaging before DAA initiation. Future studies should evaluate optimal timing of DAA therapy after HCC CR and whether this is associated with differential recurrence rates. Although prior single arm studies suggested HCC recurrences after DAA therapy might be more aggressive than expected,9,21,22 we found no difference between DAAtreated and untreated patients in several measures of tumor aggressiveness, including similar recurrence patterns, tumor burden, treatment eligibility, and treatment response. Our data are consistent with those of more recent studies,
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which have found most recurrences are detected at an early stage and can be treated with potentially curative treatments.23–26 Of note, most studies, including ours, reported intermediate outcomes such as recurrence patterns and treatment response and none evaluated HCC-related mortality. Although it remains important to monitor patients for recurrence during and after DAA therapy, available data suggest HCC surveillance intervals and treatment decisions do not need to differ from those of DAA-naïve patients. Results from our study must be interpreted in light of other limitations. First, we used imaging interpretation through routine clinical care instead of centralized imaging review. This limitation could have affected classification of HCC CR and HCC recurrence. However, all included health systems were academic centers with gastrointestinaltrained radiologists, and most centers use multidisciplinary tumor boards.27,28 Our results were consistent across all types of HCC treatment, including surgical resection, which would be less prone to misclassification of CR, suggesting this was not a major issue. Second, there is a possibility of ascertainment bias given the retrospective nature of the study and lack of strict surveillance protocol across sites. This might have led to misclassification of early vs late recurrences and missed cases of recurrence. However, standard practice at each site is to perform surveillance with cross-sectional imaging every 3–6 months in all patients after HCC CR and adherence with surveillance for cancer recurrence is typically higher than screening for incident tumors.29,30 Third, although we performed several analyses including propensity score analyses, there is potential for residual confounding. For example, DAA-treated patients were more likely to be non-Hispanic white and had less portal hypertension than untreated patients, which could affect results if these factors also influence risk of HCC recurrence. Fourth and perhaps most importantly, our study’s primary outcome was HCC recurrence; however this is only one aspect of prognosis after HCC treatment. DAA therapy is known to result in improvements in portal hypertension and liver dysfunction, which has been shown to be a major driver of prognosis in patients with a history of HCC.31 Ongoing multicenter prospective cohort studies with longer follow-up might address some of these limitations; however, these are years away from reporting and our data can provide important insights in the interim. These limitations were judged to be outweighed by the study’s notable strengths, including its multicenter design with a large cohort of patients, rigorous statistical analysis plan, and inclusion of a contemporary untreated control group. Most prior studies evaluating HCC recurrence risk and patterns after DAA treatment have been single-arm studies, with significant heterogeneity in recurrence estimates between studies. Further, comparisons with historical controls might not be ideal given differences between cohorts, including aging of HCV-infected cohorts and increasing prevalence of other HCC risk factors such as metabolic syndrome. In summary, risk of HCC recurrence did not significantly differ between DAA-treated and untreated patients.
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901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960
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DAA Therapy and HCC Recurrence
Similarly, HCC recurrence patterns and response to treatment did not significantly differ between the 2 groups. Overall, our results suggest use of DAA therapies is safe and potentially beneficial in HCV-infected patients with a history of HCC.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/ j.gastro.2019.01.027.
References 1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142:1264– 1273.e1. 2. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol https://doi.org/ 10.1016/j.jhep.2017.08.030. E-pub ahead of print. 3. Kanwal F, Kramer J, Asch SM, et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017;153:996–1005 e1. 4. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med 2013;368:1859–1861. 5. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107:569–577; quiz 578. 6. Tabrizian P, Jibara G, Shrager B, et al. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg 2015;261:947–955. 7. Singal AG, Volk ML, Jensen D, et al. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8:280–288, e1. 8. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCVrelated cirrhosis treated with direct-acting antivirals. J Hepatol 2016;65:727–733. 9. Reig M, Boix L, Marino Z, et al. Liver cancer emergence associated with antiviral treatment: an immune surveillance failure? Semin Liver Dis 2017;37:109–118. 10. Saraiya N, Yopp AC, Rich NE, et al. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther 2018;48:127–137. 11. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358–380. 12. Cho IS, Chae YR, Kim JH, et al. Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study. BMC Med Res Methodol 2017; 17:126. 13. Gleiss A, Oberbauer R, Heinze G. An unjustified benefit: immortal time bias in the analysis of time-dependent events. Transplant Int 2018;31:125–130.
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14. Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and metaregression. J Hepatol 2017;67:1204–1212. 15. Pazzagli L, Linder M, Zhang M, et al. Methods for timevarying exposure related problems in pharmacoepidemiology: an overview. Pharmacoepidemiol Drug Saf 2018;27:148–160. 16. Kolly P, Waidmann O, Vermehren J, et al. Hepatocellular carcinoma recurrence after direct antiviral agent treatment: a European multicentre study. J Hepatol 2017; 67:876–878. 17. Minami T, Tateishi R, Nakagomi R, et al. The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. J Hepatol 2016;65:1272–1273. 18. Ogawa E, Furusyo N, Nomura H, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther 2018;47:104–113. 19. Nault JC, Colombo M. Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution. J Hepatol 2016;65:663–665. 20. Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology 2018;67:401–421. 21. Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther 2017;46:688–695. 22. Granata R, Di Costanzo G, Zamparelli M, et al. Hepatocellular carcinoma recurrence rate in HCV infected patients treated with direct antiviral agents. A single center experience. J Hepatol 2017;66:S717. 23. Yasui Y, Kurosaki M, Wang W, et al. Direct acting antivirals did not increase early recurrences after curative treatment of HCV related hepatocellular carcinoma in comparison with IFN-based treatment. J Hepatol 2017; 66:S748. 24. Okhi T, Yoshida H, Goto E, et al. Direct acting antiviral therapy after curative treatment of hepatocellular carcinoma improved recurrence free survival rate. Hepatology 2017;66:759A. 25. Minami T, Tateishi R, Wake T. Hepatocellular carcinoma recurrence after curative treatments in patients with chronic hepatitis C who underwent direct-acting antiviral therapy. Hepatology 2017;66:760A–761A. 26. Sangiovanni A, Alimenti E, Biganzoli E, et al. IFN-free DAA treatment of cirrhotic HCV patients with or without history of HCC: a multi-center prospective trial in Italy. Hepatology 2017;66:734A–735A. 27. Serper M, Taddei TH, Mehta R, et al. Association of provider specialty and multidisciplinary care with hepatocellular carcinoma treatment and mortality. Gastroenterology 2017;152:1954–1964. 28. Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol 2014;21:1287–1295.
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1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080
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29. Boas FE, Do B, Louie JD, et al. Optimal imaging surveillance schedules after liver-directed therapy for hepatocellular carcinoma. J Vasc Interv Radiol 2015; 26:69–73. 30. Singal AG, Yopp A, Skinner C S, et al. Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review. J Gen Intern Med 2012; 27:861–867. 31. Cabibbo G, Petta S, Barbara M, et al. Hepatic decompensation is the major driver of death in HCVinfected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol 2017;67: 65–71.
Received October 4, 2018. Accepted January 9, 2019. Reprint requests Address requests for reprint to: Amit G. Singal, MD, MS, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, 5959 Harry Hines Boulevard, PO Box 1, Suite 420, Dallas, Texas 75390-8887. e-mail: [email protected]. Acknowledgments Author contributions: Amit G. Singal had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Amit G. Singal and Neehar D. Parikh conceived and designed the study. All authors acquired, analyzed, and interpreted the data. Amit G. Singal drafted the manuscript. All authors critically revised the manuscript for important intellectual content. Amit G. Singal, Neehar D. Parikh obtained funding. Amit G. Singal and Neehar D. Parikh provided administrative, technical, and material support. Amit G. Singal supervised the study.
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Conflicts of interest Amit G. Singal was on the speaker’s bureau for Gilead, Bayer, and Bristol Meyers Squibb. He has served on advisory boards for Gilead, Abbvie, Bayer, Eisai, Wako Diagnostics, Roche, and Exact Sciences. He serves as a consultant to Bayer, Eisai, Roche, and Glycotest. He has received research funding from Gilead and AbbVie. Neil Mehta has received research funding from Wako Diagnostics. Anjana Pillai serves as a consultant and is on the speaker’s bureau for Eisai and BTG. Jordan J. Feld has received research support from Gilead, AbbVie, Merck, and Janssen. Binu V. John has served on advisory boards for Eisai. Catherine Frenette is on the speaker’s bureaus for Bayer, Bristol Meyers Squibb, Gilead, Merck, AbbVie, and Eisai. She served on advisory boards for Gilead, Eisai, and Wako. She served as a consultant for Bayer and Gilead. She received research funding from Bayer. Parvez Mantry is on the speaker’s bureaus and served on advisory boards for Gilead, Abbvie, Bayer, BMS, Eisai, Merck, and BTG. He has received research funding from Gilead and Sirtex. Michael Leise has received research funding from AbbVie. Kalyan Ram Bhamidimarri serves as a scientific advisory board member for Gilead, Merck, and AbbVie. He has received research funding from Gilead. Laura Kulik is on the speaker’s bureau for Eisai, Gilead, and Dova. She serves as an advisory board member for BMS, Eisai, Bayer, and Exelixis. Reena Salgia is on the speaker’s bureau for Bayer. She has served on advisory boards for Bayer, Eisai, and Exelixis. Sanjaya K. Satapathy has received research support from Gilead and Bayer. He has served on advisory boards or as a consultant for AbbVie and Gilead. Robert Wong is on the speaker’s bureau, served as consultant and on advisory boards, and has received research funding from Gilead. He also has received research funding from AbbVie. He was on the speaker’s bureau for Bayer. Neehar D. Parikh serves as a consultant to Exelexis and Bristol-Myers Squibb. He has served on advisory boards for Eisai and Bayer. None of the other authors have any relevant conflicts of interest. Funding This study was conducted with support from the National Cancer Institute (RO1 Q4 CA222900) and grant support from AbbVie. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or AbbVie. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript.
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1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200
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1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260
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DAA Therapy and HCC Recurrence
Supplemental Table 1.Subgroup Analysis for Association Between DAA Therapy and HCC Recurrence Description HCC recurrence Overall Tumor stage Within Milan criteria Beyond Milan criteria HCC treatment Surgical resection Local ablative therapy TACE, TARE, SBRT SVR status Achieved SVR Did not achieve SVR Timing of DAA initiation Within 6 mo after CR Delayed >6 mo after CR Early HCC recurrence Overall Tumor stage Within Milan criteria Beyond Milan criteria HCC treatment Surgical resection Local ablative therapy TACE, TARE, SBRT SVR status Achieved SVR Did not achieve SVR Timing of DAA initiation Within 6 mo after CR Delayed >6 mo after CR
Unadjusted HR (95% CI)
Adjusted HR (95% CI)
0.79 (0.63–1.00)
0.90 (0.70–1.16)
0.83 (0.64–1.07) 0.68 (0.40–1.16)
0.92 (0.69–1.23) 0.71 (0.35–1.45)
0.59 (0.32–1.08) 0.85 (0.59–1.23) 0.80 (0.55–1.15)
0.61 (0.28–1.32) 0.92 (0.59–1.44) 0.90 (0.62–1.31)
0.77 (0.60–0.98) 0.80 (0.48–1.33)
0.86 (0.66–1.13) 0.91 (0.56–1.46)
0.77 (0.59–1.01) 0.85 (0.61–1.18)
0.90 (0.67–1.21) 0.90 (0.64–1.27)
0.81 (0.60–1.10)
0.96 (0.70–1.34)
0.82 (0.58–1.15) 0.79 (0.41–1.50)
0.97 (0.66–1.43) 1.07 (0.47–2.43)
0.61 (0.25–1.51) 0.87 (0.54–1.41) 0.78 (0.50–1.22)
0.99 (0.25–4.02) 0.99 (0.54–1.81) 0.92 (0.56–1.50)
0.76 (0.55–1.05) 0.77 (0.34–1.71)
0.90 (0.64–1.27) 0.80 (0.36–1.77)
0.86 (0.63–1.18) 0.51 (0.21–1.25)
1.05 (0.74–1.48) 0.56 (0.22–1.38)
SBRT, stereotactic body radiation therapy; SVR, sustained virologic response; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.
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10.e1
1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320
Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study Q5
Amit G. Singal,1 Nicole E. Rich,1 Neil Mehta,2 Andrea Branch,3 Anjana Pillai,4 Maarouf Hoteit,5 Michael Volk,6 Mobolaji Odewole,1 Steven Scaglione,7,8 Jennifer Guy,9 Adnan Said,10 Jordan J. Feld,11 Binu V. John,12 Catherine Frenette,13 Parvez Mantry,14 Amol S. Rangnekar,15 Omobonike Oloruntoba,16 Michael Leise,17 Janice H. Jou,18 Kalyan Ram Bhamidimarri,19 Laura Kulik,20 Tram Tran,21 Hrishikesh Samant,22 Renumathy Dhanasekaran,23 Andres Duarte-Rojo,24 Reena Salgia,25 Sheila Eswaran,26 Prasun Jalal,27 Avegail Flores,28 Sanjaya K. Satapathy,29 Robert Wong,30 Annsa Huang,2 Suresh Misra,3 Myron Schwartz,3 Robert Mitrani,5 Sasank Nakka,6 Wassim Noureddine,6 Chanda Ho,9 Venkata R. Konjeti,12 Alexander Dao,15 Kevin Nelson,17 Kelly Delarosa,21 Usman Rahim,23 Meher Mavuram,22 Jesse J. Xie,31 Caitlin C. Murphy,1,§ and Neehar D. Parikh32,§ 1
Q1
Division of Digestive and Liver Disease, UT Southwestern Medical Center; 2Division of Gastroenterology, University of California San Francisco; 3Department of Medicine, Icahn School of Medicine at Mount Sinai; 4Division of Gastroenterology, Hepatology and Nutrition, University of Chicago; 5Division of Gastroenterology and Hepatology, University of Pennsylvania; 6 Transplantation Institute and Division of Gastroenterology, Loma Linda University Health; 7Division of Hepatology, Loyola University Medical Center and 8Edward Hines Veterans Affairs; 9Department of Transplantation, California Pacific Medical Center; 10Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine; 11Toronto Center for Liver Disease, Toronto General Hospital; 12Division of Gastroenterology and Hepatology, McGuire VA Medical Center; 13Division of Organ Transplantation, Scripps Green Hospital; 14Liver Institute at Methodist Dallas; 15Division of Gastroenterology, Georgetown University Hospital; 16Division of Gastroenterology and Hepatology, Duke University Health Center; 17Division of Gastroenterology and Hepatology, Mayo Clinic; 18Division of Gastroenterology and Hepatology, Oregon Health and Science University; 19Division of Hepatology, University of Miami Miller School or Medicine; 20Division of Hepatology, Northwestern University; 21Liver Disease and Transplant Center, Cedars-Sinai Medical Center; 22Division of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center; 23Division of Gastroenterology and Hepatology, Stanford University; 24Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences; 25Division of Gastroenterology and Hepatology, Henry Ford Hospital; 26Division of Gastroenterology, Rush Medical College; 27Division of Abdominal Transplantation, Baylor College of Medicine; 28Division of Gastroenterology, Washington University School of Medicine; 29Division of Transplant Surgery, University of Tennessee Health Science Center; 30Division of Gastroenterology and Hepatology, Alameda Health System; 31Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences; 32Division of Gastroenterology and Hepatology, University of Michigan
Direct-Acting Antiviral Therapy is not Associated with HCC Recurrence: A Multicenter North American Cohort Study Conflicting data on whether direct acting antiviral hepatitis C treatment impacts the risk of hepatocellular carcinoma recurrence
Methods: 31 centers in North America including patients with HCV-related HCC with complete radiographic response
Results: 304 Treated with DAAs 489 Treatment naïve HCV DAA therapy has no impact on: HCV related HCC
DAA therapy for HCV
HCC with complete response p
?
Recurrent HCC
• Overall HCC recurrence (aHR: 0.90 95% CI: 0.90-1.17) • Early HCC recurrence (aHR: 0.96 95% CI: 0.69-1.33)
Aim: Do DAAs impact the risk of HCC recurrence? Singal AG et al. Gastroenterology. 2019
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BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70–1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70–1.34) after we adjusted for study site, age, sex, Child-Pugh score, a-fetoprotein level, tumor burden, and HCC treatment modality. In DAAtreated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P ¼ .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients. Keywords: Hepatitis C Virus; Liver Cancer; Recurrence; DirectActing Antiviral.
C
hronic hepatitis C virus (HCV) infection affects more than 3.2 million persons in the United States, where it is the most common cause of hepatocellular carcinoma (HCC).1 Highly effective direct-acting antiviral (DAA) therapies against HCV infection have the potential to decrease HCV-related HCC incidence2,3; however, suboptimal rates of HCV screening and treatment make this unlikely in the near future. It is estimated that 50% of patients with HCV are currently unaware of their infection and more than one fourth of patients with HCC have unrecognized HCV at time of tumor diagnosis.4 Therefore, the HCV-related HCC incidence could continue to increase over the next decade, if not longer. Patients diagnosed with HCC at an early stage are eligible for curative treatments including surgical resection or local ablative therapies; however, unlike liver transplantation, these therapies are limited by high recurrence.5,6
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WHAT YOU NEED TO KNOW BACKGROUND There are conflicting data concerning hepatocellular carcinoma (HCC) recurrence risk and aggressiveness in patients treated for hepatitis C with direct-acting antiviral (DAA) therapy. NEW FINDINGS In a large multicenter North American cohort, DAA therapy was not associated with an increased risk of HCC recurrence when compared to patients who were not treated for hepatitis C. HCC recurrence patterns, including treatment response, were also similar in DAAtreated and untreated patients. LIMITATIONS This study was limited by possible ascertainment bias for hepatocellular carcinoma recurrence, lack of centralized radiology review, and potential for residual confounding. IMPACT Treatment of hepatitis C with direct-acting antiviral therapy appears to be safe in patients who have achieved complete response to hepatocellular carcinoma therapy.
Historically, sustained viral response (SVR) using interferon (IFN)-based therapy for HCV was associated with significant decreases in HCC recurrence after curative treatment.7 However, IFN-based therapy elicited an SVR in only approximately 40%–50% of treated patients and could not be tolerated by many patients with cirrhosis. It is unclear whether DAA therapies have similar chemopreventive benefits for decreasing HCC recurrence in patients who achieved complete response (CR) to prior HCC-directed treatment. In fact, some observational data suggest potential increased risk of HCC recurrence after DAA therapy.8,9 One study reported high early tumor recurrence risk in patients with HCC who received DAA therapy.9 Of 58 patients with a CR, HCC recurred in 27% at a median follow-up of 5.7 months. However, the small cohort, lack of an untreated control arm, and short median duration of follow-up limited any definitive conclusions about harms related to HCV therapy, including which patients were at highest risk for early recurrence.10 Larger multicenter efforts, particularly those with comparator groups, are crucial to better understand the potential benefits and harms of HCV therapy with DAAs in patients with HCC. The aim of the present multicenter study was to compare overall and early HCC recurrence between DAA-treated and untreated
§
Authors share co-senior authorship.
Abbreviations used in this paper: AFP, a-fetoprotein; CI, confidence interval; CR, complete response; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IFN, interferon; IQR, interquartile range; SVR, sustained viral response. © 2019 by the AGA Institute 0016-5085/$36.00 https://doi.org/10.1053/j.gastro.2019.01.027
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patients in a large cohort of patients with CR to prior HCCdirected therapy.
Methods Study Design and Patient Population We conducted a multicenter retrospective cohort study of adult patients with HCV-related HCC who achieved HCC CR from January 2013 through December 2017. Patients were recruited from 31 health systems throughout the United States and Canada. HCC diagnosis was based on American Association for the Study of Liver Diseases criteria (ie, histologic confirmation or lesions >1 cm with characteristic appearance at imaging [arterial enhancement and delayed washout]).11 Patients were required to have liver-localized tumor burden at time of presentation, and patients with extrahepatic disease (lymph node involvement or metastatic spread) were excluded. We included patients who achieved HCC CR by surgical resection, local ablative therapies, transarterial chemoembolization or bland embolization, or transarterial radioembolization or stereotactic body radiation therapy; however, patients with CR after liver transplantation or systemic therapy were excluded. CR to HCC treatment was defined by modified Response Evaluation Criteria in Solid Tumors criteria (ie, disappearance of arterial enhancement from all HCC lesions on contrastenhanced cross-sectional imaging). We excluded patients with unknown HCC response (eg, lack of contrast-enhanced imaging after HCC treatment) and patients with HCC recurrence within 30 days of CR. Patients were categorized into DAA-treatment and untreated groups. The DAA-treatment group included patients who received DAA therapy, independent of SVR12, after HCC CR; the untreated group included those who did not receive DAA therapy. We excluded patients who received IFN-based therapy during the study period, completed DAA therapy before HCC CR, or completed DAA therapy after suspected HCC recurrence. The study was approved by the institutional review boards at each study site.
Data Collection We used a standardized data collection template to obtain demographic and clinical variables at time of HCC presentation from electronic medical records at each site for all patients, including age, sex, race–ethnicity, body mass index, presence of hepatitis B and human immunodeficiency viral coinfection, platelet count, aspartate aminotransferase, alanine aminotransferase, HCV viral load, HCV genotype, Eastern Cooperative Oncology Group performance status, and a-fetoprotein (AFP). Degree of liver dysfunction was assessed by Child-Pugh and Model for End-Stage Liver Disease scores. Tumor burden, as determined by interpretation of imaging by local radiologists at each site, was categorized as very early stage (single tumor <2 cm), early stage (single tumor <5 cm or 2–3 tumors each with <3 cm in maximum diameter), or intermediate stage (beyond early stage but without extrahepatic spread). We recorded the number of HCC-directed treatments needed to achieve CR and type of treatment leading to HCC CR. For DAA-treated patients, we collected DAA treatment regimen, time from HCC CR to DAA initiation, HCV viral load at weeks 4 and 12 of treatment, and DAA treatment outcome (ie, SVR).
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We assessed time from initial HCC CR to last imaging with confirmed CR and first imaging with HCC recurrence. For patients with HCC recurrence, we collected data on degree of liver dysfunction, type of recurrence (local vs new intrahepatic lesion), tumor burden, AFP, and type of HCC-directed treatment.
Statistical Analysis We compared treatment groups (DAA-treated and untreated) using c2 and Student t tests for categorical and continuous variables, respectively. We characterized time to recurrence from time of HCC CR. Patients in the 2 groups were followed from CR until recurrence, death, liver transplantation, or last clinic visit. Patients who initiated DAA therapy after HCC recurrence or liver transplantation were considered untreated. We estimated crude and adjusted hazard ratios (HRs) comparing patients treated with DAAs with those who were not treated with DAAs using a Cox proportional hazards regression model, with DAA therapy as a time-varying exposure. In brief, this method assigns follow-up time for patients before DAA initiation as unexposed time and time after DAA initiation as exposed time. We present crude and confounder-adjusted HRs (adjusted for study site, age, sex, Child-Pugh class, HCC tumor stage, AFP level, and type of HCC treatment). Confounders were selected a priori given their known association with DAA therapy receipt and HCC recurrence risk. We also estimated risk of early HCC recurrence by truncating follow-up time at 365 days of CR. In this analysis, patients who initiated DAA >365 days after achieving HCC CR were included in the untreated group. To account for the possibility that DAAs have a time-varying treatment effect, we compared the untreated group with patients who initiated DAA 6 months after CR and those in whom DAA therapy was delayed >6 months after CR. We also conducted secondary analyses stratified by tumor burden (within vs beyond Milan criteria), treatment leading to HCC CR (resection vs ablation vs transarterial chemoembolization and stereotactic body radiation therapy), and SVR status. To assess the robustness of the time-varying exposure approach, we performed a sensitivity analysis using a landmark approach to compare risk of HCC recurrence between DAAtreated and untreated groups. This approach avoids immortal time bias by synchronizing the start of follow-up for the treated and untreated groups.12,13 We started follow-up at 90, 120, and 180 days after CR to investigate the impact of landmark choice on the outcome. Patients who had HCC recurrence, died, underwent liver transplantation, or had a last clinic visit before the landmark point were excluded. Patients who initiated DAA therapy before the landmark were categorized as treated with DAA and those initiating DAA therapy after the landmark were included in the untreated group. To minimize potential for confounding, we computed a propensity score for each patient predicting the probability of initiating DAA conditional on patient characteristics (at CR) using multivariable logistic regression. The propensity score model included factors associated with initiating DAA therapy and/or recurrence, including study site, age, sex, Child-Pugh class, baseline tumor burden, AFP level, and treatment leading to CR. We estimated crude and adjusted (by inverse probability of treatment weights) HRs comparing patients treated with DAAs and those who were untreated using a Cox proportional hazards regression model.
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All tests were 2-sided and performed at the 5% significance level. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).
Results Patient Characteristics
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Selection of the study population is illustrated in Figure 1. We initially identified 1075 patients with HCVinfected HCC who achieved CR to HCC-directed therapy from January 2013 through December 2017. After excluding 225 patients who initiated DAA therapy before CR to HCC therapy, 850 patients remained. We excluded an additional 45 patients with DAA initiation and 12 patients with HCC recurrence within 30 days of HCC CR. A total of 793 patients were included in the final analysis, of whom 304 had been treated with DAA therapy and 489 were untreated. Patient demographics are presented in Table 1. Median age was 61.6 years. Most patients were men and nonHispanic white. At time of HCC diagnosis, nearly three fourths of patients had unifocal HCC and more than 80% were within Milan criteria. More than 50% of patients achieved HCC CR from locoregional therapy such as transarterial chemoembolization, whereas one third achieved CR from local ablation and 14% from surgical resection. Median time from HCC diagnosis to treatment was 2.7 months (interquartile range [IQR] 1.4–5.6) and median time from treatment to HCC CR confirmation was 1.6 months (IQR 1.1– 3.2). DAA-treated patients were older, had more preserved liver function (larger proportion with compensated cirrhosis and less portal hypertension), and were more likely to have achieved HCC CR by resection than untreated patients; however, the 2 groups had similar tumor burden at presentation, with no significant difference in the proportion presenting within Milan criteria. A larger proportion of DAA-untreated patients were listed and underwent liver transplantation than DAA-treated patients (29.4% vs 18.8%; P ¼ .001).
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Median time from HCC CR to DAA initiation was 5.8 months (IQR 3.0–11.5), with 25.0% treated within 3 months, 26.3% within 3–6 months, 24.7% treated within 6– 12 months, 18.4% treated within 12–24 months, and 5.6% treated more than 24 months after HCC CR confirmation. Most patients had genotype 1 HCV infection, and the most common DAA regimens were sofosbuvir and ledipasvir with or without ribavirin and sofosbuvir with ribavirin. SVR12 was documented in 81.8% of DAA-treated patients, with no significant differences by HCV genotype (P ¼ .16), DAA regimen (P ¼ .11), or time to DAA treatment after HCC CR (P ¼ .44).
Time to HCC Recurrence Over a median follow-up of 10.4 months (IQR 5.3–20.8), there were 416 recurrences, including 128 after initiation of DAA treatment and 288 in untreated patients. DAA therapy, when analyzed as a binary exposure, was associated with lower risk of HCC recurrence (HR 0.32, 95% confidence interval [CI] 0.25–0.41) after adjusting for study site, age, sex, Child-Pugh score, AFP level, initial tumor burden, and HCC therapy. The median time to recurrence in DAA-treated patients was 13.2 months (IQR 8.4–21.8) compared with 6.0 months (IQR 3.6–10.6) for untreated patients. However, after accounting for time-varying exposure, DAA therapy was no longer associated with HCC recurrence in crude (HR 0.79, 95% CI 0.63–1.00) and adjusted (HR 0.90, 95% CI 0.70–1.16) analyses. The propensity score model showed similar results, with DAA therapy not associated with HCC recurrence risk (HR 0.91, 95% CI 0.69–1.19). In sensitivity analyses using a landmark approach to minimize immortal time bias, DAA therapy was not significantly associated with increased or decreased risk of HCC recurrence. These results were consistent whether follow-up was started at 90 days (HR 0.92, 95% CI 0.60–1.41), 120 days (HR 0.99, 95% CI 0.66–1.48), or 180 days (HR 0.98, 95% CI 0.69–1.40) from HCC CR (Figure 2).
Figure 1. Study cohort inclusion and exclusion diagram.
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421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480
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Table 1.Patient Characteristics Variablea
DAA-treated (n ¼ 304)
DAA-untreated (n ¼ 489)
Age at time of complete response (y) Sex (% men) Race–ethnicity Non-Hispanic white Hispanic white Black Other Missing HCC nodules at diagnosis 1 2 3 4 Maximum HCC diameter (cm) at diagnosis HCC within Milan criteria at diagnosis AFP at time of HCC diagnosis (ng/mL) Treatment leading to CR Resection Local ablation TACE TARE, SBRT, other Missing HCC therapies required to achieve CR 1 2 3 Missing Child-Pugh class at CR A B C Presence of ascites Presence of hepatic encephalopathy Platelet count at CR Bilirubin at CR (mg/dL) HCV genotype 1 2 3 4–6 Missing Viral coinfection Hepatitis B virus HIV DAA regimenb Sofosbuvir þ ledipasvir Sofosbuvir Simeprevir þ sofosbuvir Sofosbuvir þ velpatasvir Daclatasvir þ sofosbuvir Ombitasvir þ partiprevir þ ritonavir þ dasabuvir Elbasavir ¼ grazoprevir Other DAA regimen duration <12 wk 12 wk >12–<24 wk 24 wk >24 wk Missing
62.4 (59.0–66.5) 214 (70.4)
61.3 (57.4–65.2) 373 (76.3)
156 44 59 13 32
(51.3) (14.5) (19.4) (4.3) (10.5)
191 82 103 24 89
(39.1) (16.8) (21.1) (4.9) (18.2)
231 56 12 5 2.4 246 18.5
(76.0) (18.4) (4.0) (1.6) (1.7–3.5) (81.7) (7.6–64.7)
343 99 32 15 2.5 400 18.4
(70.1) (20.2) (6.5) (3.1) (2.0–3.6) (82.3) (7.7–67.3)
64 107 107 26 0
(21.1) (35.2) (35.2) (8.5) (0)
47 157 253 30 2
(9.6) (32.1) (51.7) (6.1) (0.4)
189 68 37 10
(62.1) (22.4) (12.2) (3.3)
243 125 86 35
(49.7) (25.6) (17.6) (7.1)
191 96 17 75 42 112 1.0
(62.8) (31.6) (5.6) (24.7) (13.8) (76–163) (0.6–1.7)
244 188 57 177 106 89 1.2
(49.9) (38.4) (11.7) (36.2) (21.6) (60–135) (0.7–2.0)
240 26 31 5 2
(78.9) (8.6) (10.2) (1.6) (0.7)
331 17 70 17 54
(67.7) (3.5) (14.3) (3.5) (11.0)
P value .03 .07 .005
.17
.85 .84 .66 <.001
.04
<.001
.001 .006 <.001 .32 <.001
.10 8 (2.6) 7 (2.3)
5 (1.0) 8 (1.6)
188 49 27 15 10 6 3 6
(61.8) (16.2) (8.9) (4.9) (3.3) (2.0) (1.0) (1.9)
N/A
10 169 18 97 6 4
(3.3) (55.6) (5.9) (31.9) (2.0) (1.3)
N/A
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481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540
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541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600
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Table 1. Continued Variablea Time from HCC CR to DAA <3 mo >3–6 mo >6–12 mo >12–24 mo >24 mo
DAA-treated (n ¼ 304) 76 80 75 56 17
DAA-untreated (n ¼ 489)
(25.0) (26.3) (24.7) (18.4) (5.6)
P value
N/A
HIV, human immunodeficiency virus; N/A, not applicable; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization. a Continuous data are presented as median (IQR). b All DAA regimens are with or without ribavirin.
Results were consistent across all subgroup analyses, stratified by tumor burden and treatment type leading to CR (Supplemental Table 1). Although DAA therapy was associated with lower recurrence risk in the subgroup of patients who achieved CR after resection, this difference did not reach statistical significance (HR 0.61, 95% CI 0.28–1.32). We also found no difference in the association between DAA therapy and HCC recurrence risk by SVR status, although the number of patients who did not achieve SVR was small, or timing of DAA therapy in relation to CR (Supplemental Table 1). In a sensitivity analysis excluding 27 patients with prior HCC recurrence, DAA therapy continued to have no significant association with HCC recurrence (HR 0.91, 95% CI 0.70–1.18). Compared with untreated patients, DAA therapy was not associated with differential recurrence risk in patients who initiated DAA therapy within 6 months of CR (HR 0.90, 95% CI 0.67–1.21) or those who delayed DAA >6 months after CR (HR 0.90, 95% CI 0.64–1.27). The
proportions of patients with HCC recurrence were 44.0% for those initiating DAA within 3 months of HCC CR, 50.0% for those initiating DAA 4–6 months after HCC CR, and 36.9% for those initiating DAA after 6 months.
Time to Early HCC Recurrence There were 52 patients (17.1%) in the DAA-treated group and 227 (46.4%) in the untreated group who developed early recurrence within 365 days of HCC CR. DAA therapy, when analyzed as a binary exposure, was associated with lower risk of early HCC recurrence (HR 0.44, 95% CI 0.32–0.61) after adjusting for study site, age, sex, ChildPugh score, AFP level, initial tumor burden, and HCC therapy. However, accounting for time-varying exposure, there was no significant association between DAA therapy and early HCC recurrence in crude (HR 0.81, 95% CI 0.60–1.10) or adjusted (HR 0.96, 95% CI 0.70–1.34) analyses. The propensity score model showed similar results, with DAA
print & web 4C=FPO
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Figure 2. Time to HCC recurrence, stratified by receipt of DAA HCV therapy, and landmark analysis of 90 days after HCC CR.
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Q3
661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720
721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
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therapy not associated with increased HCC recurrence (HR 0.96, 95% CI 0.67–1.38). Results of the time-varying exposure analysis were consistent in subgroup analyses, stratified by tumor burden and treatment leading to CR (Supplemental Table 1). Similarly, there was no difference in the association between DAA therapy and early HCC recurrence risk by SVR status. Compared with untreated patients, risk of early HCC recurrence appeared to potentially differ by timing of DAA therapy. DAA initiation within 6 months of HCC CR was not associated with early HCC recurrence (HR 1.05, 95% CI 0.74–1.48). Although patients who delayed DAA therapy >6 months after HCC CR had lower risk of early HCC recurrence (HR 0.56, 95% CI 0.22–1.38), this did not reach statistical significance likely related to the small sample.
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recurrence presented as local recurrence, new intrahepatic lesion, and extrahepatic disease in 28.9%, 55.5%, and 7.8% of DAA-treated patients versus 38.2%, 50.3%, and 5.9% of untreated patients, respectively. In DAA-treated and untreated groups, most recurrences were detected at an early stage (74.2 vs 78.8% within Milan criteria, respectively; 70.3% vs 67.7% at Barcelona Clinic Liver Cancer stage 0/A, respectively). A larger proportion of DAA-treated patients received potentially curative therapy (transplantation, resection, or ablation) for HCC recurrence compared with untreated patients (32.0% vs 24.6%), although this did not reach statistical significance (P ¼ .15). Similarly, there was no significant difference in the proportion that achieved CR or partial response to treatment of HCC recurrence.
Discussion Recurrence Patterns and Treatment Response Recurrence patterns did not significantly differ between DAA-treated and untreated patients (Table 2). HCC
To the best of our knowledge, this study represents the largest study to date comparing HCC recurrence risk between DAA-treated patients and a contemporary group of
Table 2.HCC Recurrence Patterns and Treatment Variablea Type of recurrence Local Distant Missing HCC nodules 1 2 3 4 Infiltrative Missing Maximum tumor diameter (cm) Vascular invasion Distant metastases HCC within Milan criteria BCLC tumor stage 0/A B C D Missing Treatment of HCC recurrence Liver transplantation Surgical resection Local ablation TACE, TARE, SBRT Systemic therapy Best supportive care Missing Response to HCC treatment CR Partial response Stable disease Progressive disease Unknown or missing
DAA-treated (n ¼ 128)
DAA-untreated (n ¼ 288)
P value .33
37 (28.9) 81 (63.3) 10 (7.8)
110 (38.2) 162 (55.3) 16 (5.5)
77 30 8 8 4 1 1.8 7 11 95
(60.1) (23.4) (6.3) (6.3) (3.1) (0.8) (1.2–2.7) (5.4) (8.6) (74.2)
173 61 20 15 15 5 1.6 10 17 227
(60.1) (21.2) (6.9) (5.2) (5.2) (1.4) (1.2–2.5) (3.5) (5.9) (78.8)
90 11 16 11 0
(70.3) (8.6) (12.5) (8.6) (0)
195 17 28 46 2
(67.7) (5.9) (9.7) (16.0) (0.7)
10 2 29 55 8 21 3
(7.8) (1.6) (22.6) (43.0) (6.3) (16.4) (2.3)
18 11 42 153 11 47 6
(6.2) (3.8) (14.6) (53.1) (3.9) (16.3) (2.1)
43 15 15 17 38
(33.6) (11.7) (11.7) (13.3) (29.7)
91 27 40 57 73
(31.6) (9.4) (13.9) (19.8) (25.3)
.87
.29 .34 .28 .23 .16
.15
.31
BCLC, Barcelona Clinic Liver Cancer; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization. a Continuous data are presented as median (IQR).
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781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840
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Q2
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841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900
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untreated patients. We found DAA therapy was not associated with overall or early HCC recurrence after CR. Similarly, we did not observe any differences in patterns or aggressiveness of HCC recurrence between DAA-treated and untreated patients. A prior meta-analysis of relevant literature found no association between DAA therapy and de novo or recurrent HCC.14 Similarly, an updated meta-analysis identified 9 studies that compared HCC recurrence in DAA-treated patients (n ¼ 947) with IFN-treated (n ¼ 210) and/or untreated (n ¼ 641) patients.10 Among studies reporting relative risk of recurrence, DAA-treated patients had a lower pooled recurrence risk than untreated patients (odds ratio 0.55, 95% CI 0.25–0.85); however, most prior studies analyzed DAA treatment as a fixed binary exposure, which ignores the time dependency of DAA exposure and potentially leads to inaccurate HR estimates.15 Our results highlight the importance of analyzing DAA therapy as a time-varying exposure, because we found significant differences compared with the binary exposure analysis. There is a tendency for patients with early HCC recurrence to be artifactual members of the untreated group simply because early recurrence decreases the time available to start DAAs before recurrence. Because cohort studies also can be limited by immortal time bias, in which HCC recurrence could not occur before DAA exposure, we also conducted landmark analyses anchored at 3 different time points. Although we found decreased risk of HCC recurrence in DAA-treated patients in binary analyses, this difference was mitigated in time-varying analyses. Although we found no association between DAA therapy and risk of HCC recurrence, we found the risk of early recurrence can differ by timing of DAA therapy. Prior studies have reported an association between HCC recurrence and timing of DAA therapy initiation, with later initiation associated with lower HCC recurrence risk16–18; however, the mechanism underlying this association remains unclear. It has been hypothesized that early DAA therapy and rapid viral clearance might quickly blunt hepatic inflammation, resulting in an “immune break” that allows unchecked growth of microscopic tumor clones19; however, this has yet to be proved. Alternatively, delaying DAA therapy might allow more time for repeat imaging to verify HCC CR and minimize the chance of misclassification bias. This is important because more than 50% of subcentimeter lesions and more than 25% of 1- to 2-cm lesions can be missed by 1-time computed tomography or magnetic resonance imaging.20 Therefore, many “early HCC recurrences” might actually be pre-existing HCC cases that were preclinical at imaging before DAA initiation. Future studies should evaluate optimal timing of DAA therapy after HCC CR and whether this is associated with differential recurrence rates. Although prior single arm studies suggested HCC recurrences after DAA therapy might be more aggressive than expected,9,21,22 we found no difference between DAAtreated and untreated patients in several measures of tumor aggressiveness, including similar recurrence patterns, tumor burden, treatment eligibility, and treatment response. Our data are consistent with those of more recent studies,
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which have found most recurrences are detected at an early stage and can be treated with potentially curative treatments.23–26 Of note, most studies, including ours, reported intermediate outcomes such as recurrence patterns and treatment response and none evaluated HCC-related mortality. Although it remains important to monitor patients for recurrence during and after DAA therapy, available data suggest HCC surveillance intervals and treatment decisions do not need to differ from those of DAA-naïve patients. Results from our study must be interpreted in light of other limitations. First, we used imaging interpretation through routine clinical care instead of centralized imaging review. This limitation could have affected classification of HCC CR and HCC recurrence. However, all included health systems were academic centers with gastrointestinaltrained radiologists, and most centers use multidisciplinary tumor boards.27,28 Our results were consistent across all types of HCC treatment, including surgical resection, which would be less prone to misclassification of CR, suggesting this was not a major issue. Second, there is a possibility of ascertainment bias given the retrospective nature of the study and lack of strict surveillance protocol across sites. This might have led to misclassification of early vs late recurrences and missed cases of recurrence. However, standard practice at each site is to perform surveillance with cross-sectional imaging every 3–6 months in all patients after HCC CR and adherence with surveillance for cancer recurrence is typically higher than screening for incident tumors.29,30 Third, although we performed several analyses including propensity score analyses, there is potential for residual confounding. For example, DAA-treated patients were more likely to be non-Hispanic white and had less portal hypertension than untreated patients, which could affect results if these factors also influence risk of HCC recurrence. Fourth and perhaps most importantly, our study’s primary outcome was HCC recurrence; however this is only one aspect of prognosis after HCC treatment. DAA therapy is known to result in improvements in portal hypertension and liver dysfunction, which has been shown to be a major driver of prognosis in patients with a history of HCC.31 Ongoing multicenter prospective cohort studies with longer follow-up might address some of these limitations; however, these are years away from reporting and our data can provide important insights in the interim. These limitations were judged to be outweighed by the study’s notable strengths, including its multicenter design with a large cohort of patients, rigorous statistical analysis plan, and inclusion of a contemporary untreated control group. Most prior studies evaluating HCC recurrence risk and patterns after DAA treatment have been single-arm studies, with significant heterogeneity in recurrence estimates between studies. Further, comparisons with historical controls might not be ideal given differences between cohorts, including aging of HCV-infected cohorts and increasing prevalence of other HCC risk factors such as metabolic syndrome. In summary, risk of HCC recurrence did not significantly differ between DAA-treated and untreated patients.
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Similarly, HCC recurrence patterns and response to treatment did not significantly differ between the 2 groups. Overall, our results suggest use of DAA therapies is safe and potentially beneficial in HCV-infected patients with a history of HCC.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/ j.gastro.2019.01.027.
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14. Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and metaregression. J Hepatol 2017;67:1204–1212. 15. Pazzagli L, Linder M, Zhang M, et al. Methods for timevarying exposure related problems in pharmacoepidemiology: an overview. Pharmacoepidemiol Drug Saf 2018;27:148–160. 16. Kolly P, Waidmann O, Vermehren J, et al. Hepatocellular carcinoma recurrence after direct antiviral agent treatment: a European multicentre study. J Hepatol 2017; 67:876–878. 17. Minami T, Tateishi R, Nakagomi R, et al. The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. J Hepatol 2016;65:1272–1273. 18. Ogawa E, Furusyo N, Nomura H, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther 2018;47:104–113. 19. Nault JC, Colombo M. Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution. J Hepatol 2016;65:663–665. 20. Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology 2018;67:401–421. 21. Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther 2017;46:688–695. 22. Granata R, Di Costanzo G, Zamparelli M, et al. Hepatocellular carcinoma recurrence rate in HCV infected patients treated with direct antiviral agents. A single center experience. J Hepatol 2017;66:S717. 23. Yasui Y, Kurosaki M, Wang W, et al. Direct acting antivirals did not increase early recurrences after curative treatment of HCV related hepatocellular carcinoma in comparison with IFN-based treatment. J Hepatol 2017; 66:S748. 24. Okhi T, Yoshida H, Goto E, et al. Direct acting antiviral therapy after curative treatment of hepatocellular carcinoma improved recurrence free survival rate. Hepatology 2017;66:759A. 25. Minami T, Tateishi R, Wake T. Hepatocellular carcinoma recurrence after curative treatments in patients with chronic hepatitis C who underwent direct-acting antiviral therapy. Hepatology 2017;66:760A–761A. 26. Sangiovanni A, Alimenti E, Biganzoli E, et al. IFN-free DAA treatment of cirrhotic HCV patients with or without history of HCC: a multi-center prospective trial in Italy. Hepatology 2017;66:734A–735A. 27. Serper M, Taddei TH, Mehta R, et al. Association of provider specialty and multidisciplinary care with hepatocellular carcinoma treatment and mortality. Gastroenterology 2017;152:1954–1964. 28. Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol 2014;21:1287–1295.
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29. Boas FE, Do B, Louie JD, et al. Optimal imaging surveillance schedules after liver-directed therapy for hepatocellular carcinoma. J Vasc Interv Radiol 2015; 26:69–73. 30. Singal AG, Yopp A, Skinner C S, et al. Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review. J Gen Intern Med 2012; 27:861–867. 31. Cabibbo G, Petta S, Barbara M, et al. Hepatic decompensation is the major driver of death in HCVinfected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol 2017;67: 65–71.
Received October 4, 2018. Accepted January 9, 2019. Reprint requests Address requests for reprint to: Amit G. Singal, MD, MS, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, 5959 Harry Hines Boulevard, PO Box 1, Suite 420, Dallas, Texas 75390-8887. e-mail: [email protected]. Acknowledgments Author contributions: Amit G. Singal had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Amit G. Singal and Neehar D. Parikh conceived and designed the study. All authors acquired, analyzed, and interpreted the data. Amit G. Singal drafted the manuscript. All authors critically revised the manuscript for important intellectual content. Amit G. Singal, Neehar D. Parikh obtained funding. Amit G. Singal and Neehar D. Parikh provided administrative, technical, and material support. Amit G. Singal supervised the study.
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Conflicts of interest Amit G. Singal was on the speaker’s bureau for Gilead, Bayer, and Bristol Meyers Squibb. He has served on advisory boards for Gilead, Abbvie, Bayer, Eisai, Wako Diagnostics, Roche, and Exact Sciences. He serves as a consultant to Bayer, Eisai, Roche, and Glycotest. He has received research funding from Gilead and AbbVie. Neil Mehta has received research funding from Wako Diagnostics. Anjana Pillai serves as a consultant and is on the speaker’s bureau for Eisai and BTG. Jordan J. Feld has received research support from Gilead, AbbVie, Merck, and Janssen. Binu V. John has served on advisory boards for Eisai. Catherine Frenette is on the speaker’s bureaus for Bayer, Bristol Meyers Squibb, Gilead, Merck, AbbVie, and Eisai. She served on advisory boards for Gilead, Eisai, and Wako. She served as a consultant for Bayer and Gilead. She received research funding from Bayer. Parvez Mantry is on the speaker’s bureaus and served on advisory boards for Gilead, Abbvie, Bayer, BMS, Eisai, Merck, and BTG. He has received research funding from Gilead and Sirtex. Michael Leise has received research funding from AbbVie. Kalyan Ram Bhamidimarri serves as a scientific advisory board member for Gilead, Merck, and AbbVie. He has received research funding from Gilead. Laura Kulik is on the speaker’s bureau for Eisai, Gilead, and Dova. She serves as an advisory board member for BMS, Eisai, Bayer, and Exelixis. Reena Salgia is on the speaker’s bureau for Bayer. She has served on advisory boards for Bayer, Eisai, and Exelixis. Sanjaya K. Satapathy has received research support from Gilead and Bayer. He has served on advisory boards or as a consultant for AbbVie and Gilead. Robert Wong is on the speaker’s bureau, served as consultant and on advisory boards, and has received research funding from Gilead. He also has received research funding from AbbVie. He was on the speaker’s bureau for Bayer. Neehar D. Parikh serves as a consultant to Exelexis and Bristol-Myers Squibb. He has served on advisory boards for Eisai and Bayer. None of the other authors have any relevant conflicts of interest. Funding This study was conducted with support from the National Cancer Institute (RO1 Q4 CA222900) and grant support from AbbVie. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or AbbVie. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript.
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Supplemental Table 1.Subgroup Analysis for Association Between DAA Therapy and HCC Recurrence Description HCC recurrence Overall Tumor stage Within Milan criteria Beyond Milan criteria HCC treatment Surgical resection Local ablative therapy TACE, TARE, SBRT SVR status Achieved SVR Did not achieve SVR Timing of DAA initiation Within 6 mo after CR Delayed >6 mo after CR Early HCC recurrence Overall Tumor stage Within Milan criteria Beyond Milan criteria HCC treatment Surgical resection Local ablative therapy TACE, TARE, SBRT SVR status Achieved SVR Did not achieve SVR Timing of DAA initiation Within 6 mo after CR Delayed >6 mo after CR
Unadjusted HR (95% CI)
Adjusted HR (95% CI)
0.79 (0.63–1.00)
0.90 (0.70–1.16)
0.83 (0.64–1.07) 0.68 (0.40–1.16)
0.92 (0.69–1.23) 0.71 (0.35–1.45)
0.59 (0.32–1.08) 0.85 (0.59–1.23) 0.80 (0.55–1.15)
0.61 (0.28–1.32) 0.92 (0.59–1.44) 0.90 (0.62–1.31)
0.77 (0.60–0.98) 0.80 (0.48–1.33)
0.86 (0.66–1.13) 0.91 (0.56–1.46)
0.77 (0.59–1.01) 0.85 (0.61–1.18)
0.90 (0.67–1.21) 0.90 (0.64–1.27)
0.81 (0.60–1.10)
0.96 (0.70–1.34)
0.82 (0.58–1.15) 0.79 (0.41–1.50)
0.97 (0.66–1.43) 1.07 (0.47–2.43)
0.61 (0.25–1.51) 0.87 (0.54–1.41) 0.78 (0.50–1.22)
0.99 (0.25–4.02) 0.99 (0.54–1.81) 0.92 (0.56–1.50)
0.76 (0.55–1.05) 0.77 (0.34–1.71)
0.90 (0.64–1.27) 0.80 (0.36–1.77)
0.86 (0.63–1.18) 0.51 (0.21–1.25)
1.05 (0.74–1.48) 0.56 (0.22–1.38)
SBRT, stereotactic body radiation therapy; SVR, sustained virologic response; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.
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