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Original Clinical Science—Liver

The Impact of Direct-acting Antivirals on Overall Mortality and Tumoral Recurrence in Patients With Hepatocellular Carcinoma Listed for Liver Transplantation: An International Multicenter Study

Gorgen, Andre MD, MSc1,2; Galvin, Zita MD1,3; Huang, Annsa C. MD4; Vinaixa, Carmen MD5; O’Rourke, Joanne M. MD6; Francoz, Claire MD7; Hansen, Bettina E. PhD8,9; Durand, François MD7; Elsharkawy, Ahmed M. MD6; Shah, Tahir MD6; Berenguer, Marina MD5; Rubin, Angel MD5; Calatayud, David MD5; Mehta, Neil MD4; Terrault, Norah A. MDMPH4; Lilly, Les B. MDMSc1,3; Selzner, Nazia MD, PhD1,3; Sapisochin, Gonzalo MD, PhD, MSc1,2

Author Information
doi: 10.1097/TP.0000000000003115

Abstract

INTRODUCTION

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis.1,2 In North America and Europe, hepatitis C virus (HCV) is the most important risk factor for the development of HCC.3 The direct-acting antivirals (DAA) for the treatment of HCV have revolutionized the field of hepatology.4,5 In recent years, DAA have become the standard of care for patients with HCV infection.6,7 Sustained virological response (SVR) after DAA has been associated with a significant reduction in the risk of de novo HCC.8-10

Despite the virological success of DAAs, conflicting data have been published about the risk of HCC recurrence when these agents are used in patients with HCC. Some studies have reported higher HCC recurrence rates in DAA-treated patients,11,12 while this has been refuted by a number of other studies.13-16 However, many of these studies are noncomparative or have lack of HCC treatment standardization and these methodological issues have been a source of criticism.17

For patients with HCC and cirrhosis, liver transplantation (LT) offers the best chance of long-term survival.18 Transplantation ensures that all patients achieve “complete response” after treatment. This is therefore a unique population to address the impact of DAA on HCC recurrence. To our knowledge, only 2 small reports have been published assessing the impact of antiviral therapies specifically on patients with HCC who underwent LT.19,20 Therefore, the question of whether the use of DAAs increases the risk of HCC recurrence after LT remains unanswered.

To contribute to this debate, we designed a retrospective cohort to assess: (1) Are DAAs associated with increased risk of mortality in patients listed for LT? (2) Are DAAs associated with increased risk of HCC recurrence post-LT? (3) Is SVR related to DAA associated with the risk of HCC recurrence post-LT? (4) Does DAA treatment impact the pattern of recurrence post-LT?

MATERIALS AND METHODS

Ethics approval was obtained from the participating centers. In some cases, local committees deemed that there was no need for local ethics approval for sharing the data.

Study Design and Patient Selection

We assessed adults (≥18 y) listed for LT between July 1, 2005, and June 30, 2015, in 5 academic LT centers. Patients were followed until December 31, 2017. We performed an intention-to-treat (ITT) analysis of patients listed for LT and patients who underwent LT were analyzed as treated. All patients were listed for LT as treatment for HCC related to HCV. HCV diagnosis was defined by the presence of HCV antibody and HCV RNA. HCC diagnosis was made according to international guidelines.21 The exposure of interest was antiviral treatment after HCC diagnosis. Patients who received antiviral treatment before the HCC diagnosis were excluded. Retransplanted patients and those with HIV and/or hepatitis B coinfection were excluded. Patients with incidental HCC were included in the study only if the antiviral was started after LT.

We recorded patients’ demographics, HCV genotype, Model for End-Stage Liver Disease score, tumor burden, pre-LT alpha-fetoprotein (AFP) levels (ng/mL), and achievement of SVR. SVR was defined as the continued absence of detectable HCV RNA for ≥12 weeks after completion of therapy among the patients treated with DAA and ≥6 months after the end of interferon (IFN)-based treatments. Tumor burden was assessed before LT and at the pathological specimen. Explant specimen was available for all patients. Tumor differentiation was defined according to the modified Edmondson criteria.22 Patients with necrotic tumors at explant (ie, successfully ablated tumor) were considered as having “zero” tumors and the degree of differentiation as “no viable tumor.” This study complies with the STrengthening the Reporting of OBservational studies in Epidemiology statement for retrospective studies.23

Antiviral Therapy and HCC Recurrence

To assess the impact of antiviral therapy on HCC recurrence, patients were divided into 3 groups accordingly to the antiviral they have received after the HCC diagnosis: (1) DAA-based regimens, (2) IFN-based therapies, and (3) antiviral naïve patients. Patients who had failed treatment with IFN and had subsequently been treated with a DAA were included in the DAA group. The group “antiviral naïve” was composed of patients who had not received any antiviral therapy throughout their medical history. We anticipated that patients could be treated with antiviral treatment at different time points (ie, before or after LT). Therefore, the impact of pre-LT antiviral therapy was assessed by comparing patients treated with pre-LT DAA, pre-LT IFN, and those who were HCV treatment naïve. A subgroup analysis was performed for patients who achieved SVR before LT (ie, pre-LT DAA-SVR versus pre-LT IFN-SVR). Similarly, the impact of post-LT antiviral therapy was assessed by comparing patients treated with post-LT DAA, post-LT IFN, and those who were HCV treatment naïve. A subgroup analysis was performed for patients who achieved SVR after LT (ie, post-LT DAA-SVR versus post-LT IFN-SVR). For the patients treated with antivirals after LT, to avoid immortal time bias, we considered the exposure to antiviral therapies as a time-varying covariate.

Liver Transplant Criteria and Preoperative Tumor Treatment

Table S1 (SDC, http://links.lww.com/TP/B824) shows the LT criteria for HCC in each participating center. Patients with an expected waiting time >6 months could have been treated with ablation, transarterial chemoembolization, intraarterial radiation, or external radiation therapy as a bridge to LT. The decision on the treatment strategy was made according to each centers’ protocol.

Posttransplant Follow-up

The posttransplant follow-up was center-specific. Some centers used uniform-surveillance protocols, regardless of the explant characteristics, others used modified surveillance protocols according to perceived recurrence risk, while others arranged investigations depending on patients’ symptoms. Table S2 (SDC, http://links.lww.com/TP/B824) shows details on the post-LT management protocols of each participant center.

Outcome Measures

The study’s primary outcome was overall survival (ITT analysis). Patients were followed from listing for LT to death. Dropout from the waiting list was defined as the withdrawal from the waiting list by any reason other than LT. Dropout rates were compared between the groups of antiviral therapies. The secondary outcome was HCC recurrence. Patients who underwent LT were followed from LT to tumoral recurrence, death, or the end of study. Tumoral recurrence was diagnosed by imaging (either computed tomography or magnetic resonance). When imaging was not conclusive, a biopsy was performed. The pattern of recurrence (time-to-recurrence and recurrence site) was considered as potential outcomes. The recurrence location was classified as intrahepatic or extrahepatic. Intrahepatic recurrence was defined as HCC recurrence in the transplanted liver. All other sites of recurrence were classified as extrahepatic. Patients with hepatic and extrahepatic recurrence were classified as having extrahepatic recurrence. To assess the potential role of antiviral therapy on early HCC recurrence, we performed a sensitivity analysis among patients who underwent antiviral therapy within 2 years from LT.

Statistical Analysis

Continuous variables were expressed as median and interquartile range (IQR) and compared using the Kruskal-Wallis rank test. Categorical data were expressed as proportions and compared by the chi-squared test with Fisher’s correction. Patients were grouped according to the type of treatment they had received, in accordance with the study’s inclusion and exclusion criteria. For patients who received antivirals after LT, given the grouping methodology relies on the future definition of treatment for some patients, the descriptive is presented with the sole purpose of illustrating the population.

Overall survival and HCC recurrence were considered time-to-event outcomes. Patients were only assessed with regards to the antiviral treatment before the outcome. These outcomes were assessed by the Kaplan-Meier method and compared by the log-rank test. Among patients treated with antivirals after LT or those who remained antiviral naïve during the follow-up, the crude incidence rate of HCC recurrence was calculated and reported as 100 person-year derived using Poisson confidence intervals (CI). For patients treated with antivirals after LT, given that antiviral therapy is a time-dependent covariate; that is, the group’s definition was based on future characteristics, the Kaplan-Meier curves were built applying the clock reset approach, as previously described.24 Briefly, the cumulative incidence curves were built with each patients’ time of observation in each group of interest, allowing patients to “switch curves” when applicable. For this reason, the total number of patients at risk was higher than the total study’s population. These curves were presented along with the hazard ratios (HR) provided by the multivariable Cox regression. We calculated the univariable Cox regression with time-varying covariates (when appropriate). We accounted for the competing risks between HCC recurrence and death not related to HCC. The regression with competing risks was performed as previously described.25 All variables with a P < 0.20 in the univariable model were included in the multivariable model. Treatment’s effect modifications were tested by including interaction terms between treatment and well-known predictors of HCC recurrence such as tumor size, number of lesions, vascular invasion, serum AFP, and tumor differentiation. Potential center-effects on the multivariable models were accounted by center stratification in the Cox regression model. The assumptions in the regression models were not violated as assessed by cumulative incidence function graphs.25 Results of the multivariate analysis were expressed as HR with 95% CI. A P < 0.05 (2-tailored) was considered statistically significant. Statistical analyses were performed using STATA 15.0 (Stata Corp., College Station, TX).

RESULTS

During the study period, 1012 patients with HCV-HCC were listed for LT at the participating centers. At listing, 24 (2.4%) patients had been treated with DAA, 116 (11.5%) patients had been treated with IFN, and 872 (86.2%) patients were antiviral naïve. During follow-up (either while waiting or after transplant), 516 (59.0%) patients were eventually treated with DAA and 216 (24.8%) with IFN. Therefore, 142 (16.2%) patients did not receive antiviral either pre- or post-LT and were classified as antiviral naïve for the purpose of the analysis. Figure 1 summarizes the study flowchart. The median follow-up time from the time of listing was 4.0 (IQR, 2.3–6.7) years. Table 1 shows the baseline characteristics of patients.

TABLE 1. - Characteristics of patients with HCV and HCC listed for liver transplantation
Variable Overall
n = 1012
Sex, male (%) 815 (80.5)
Age at transplant (IQR) 57.6 (53.6–62.0)
Calculated MELD at transplant (IQR) 11.0 (8.5–14.0)
HCV genotype a (%)
 1 612 (69.2)
 2 37 (4.2)
 3 193 (21.8)
 4 35 (4.0)
 5 1 (0.1)
 6 6 (0.7)
Locoregional therapy, yes (%) 785 (77.6)
Size of the largest tumor, cm (IQR) 2.5 (2.0–3.3)
Number of tumors (IQR) 1 (1–2)
Milan-in, yes (%) 785 (77.6)
Serum AFP, ng/mL (IQR) 16.0 (7.0–52.7)
Antiviral treatment
 DAA before listing 24 (2.4)
 DAA during waiting time 106 (10.5)
 DAA after LT 395 (39.0)
 IFN before listing 116 (11.5)
 IFN during waiting time 28 (2.8)
 IFN after LT 105 (10.4)
 None antiviral 238 (23.5)
Overall SVR (%) 698 (69.0)
Transplanted, yes (%) 875 (86.5)
Waiting time, mo (IQR) 6.3 (3.0–11.8)
aAmong 884 patients.
AFP, alpha-fetoprotein; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; SVR, sustained virological response.

FIGURE 1.
FIGURE 1.:
Study flowchart. DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; IFN, interferon; LT, liver transplantation.

After listing, 9 of 130 (6.9%) DAA patients dropped out from the waiting list. The dropout rate was 32 of 144 (22.2%) in the IFN group and 96 of 738 (13.0%) among patients antiviral naïve (P = 0.001). The crude mortality in the ITT analysis was 5.6 (95% CI, 4.3-7.2) per 100 person-year among DAA patients, 13.1 (95% CI, 11.0-15.7) among IFN patients, and 6.2 (95% CI, 5.4-7.2) deaths per 100 person-year among patients who did not receive antivirals, P < 0.001 (Figure 2). In a multivariable regression analysis, use of DAA was not associated with increased probability of death (HR = 1.32 [95% CI, 0.96-1.81]) when compared with no antivirals. On the other hand, the use of IFN was associated with increased risk of death (HR = 3.25 [95% CI, 2.54-4.16], Table S3, SDC, http://links.lww.com/TP/B824).

FIGURE 2.
FIGURE 2.:
Survival probabilities of patients with HCV-HCC listed for LT according to the type of antiviral therapy. CI, confidence interval; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IFN, interferon; LT, liver transplantation.

Pretransplant Antiviral Therapy

Characteristics of Patients

Among the 875 patients who underwent LT, 121 (13.8%) patients had received DAA treatment, 112 (12.8%) patients had been treated with IFN, and 642 (73.4%) patients were antiviral naïve at the time of LT (Table 2). The median follow-up after LT, for pre-LT DAA group, pre-LT IFN group, and antiviral naïve group, were 2.1 (IQR, 1.2–2.6), 2.9 (IQR, 1.1–5.0), and 2.7 (IQR, 1.3–5.7) years, respectively (P = 0.001). Among patients treated with pre-LT DAA, the time span between the antiviral and the LT was 0.2 (IQR, 0.0–0.7) years, whereas among pre-LT IFN patients, it was 1.0 (IQR, 0.8–1.1) year, P < 0.001. Pre-LT DAA patients received more pre-LT locoregional therapies, had a lower tumor burden, and less frequently showed vascular invasion in their explants.

TABLE 2. - Characteristics of patients with HCV and HCC who underwent liver transplantation according to the type of antiviral treatment received before liver transplantation
Variable Overall
n = 375
HCV treatment
Pre-LT DAA
n = 121
Pre-LT IFN
n = 112
None
n = 142
P
Sex, male (%) 300 (80.0) 91 (75.2) 93 (83.0) 116 (81.7) 0.27
Age at transplant (IQR) 58.6 (54.1–63.0) 61.1 (56.5–64.1) 56.9 (51.8–61.9) 57.3 (53.4–61.7) <0.001
Calculated MELD at transplant (IQR) 10.2 (0.2–13.0) 10.0 (8.5–12.3) 9.6 (7.7–13.0) 11.1 (8.7–14.0) 0.02
HCV genotype a (%) 0.27
 1 225 (60.0) 77 (63.6) 59 (52.7) 89 (62.7)
 2 18 (4.8) 8 (6.6) 8 (7.1) 2 (1.4)
 3 73 (19.5) 23 (19.0) 25 (22.3) 25 (17.6)
 4 7 (1.9) 1 (0.8) 2 (1.8) 4 (2.8)
 5 1 (0.3) 0 (0) 0 (0) 1 (0.7)
 6 3 (0.8) 0 (0) 1 (0.9) 2 (1.4)
Pre-LT locoregional therapy (%) 295 (78.7) 114 (94.2) 81 (72.3) 100 (70.4) <0.001
Pre-LT size of the largest tumor, cm (IQR) 2.5 (2.0–3.0) 2.4 (2.0–3.0) 2.5 (1.9–3.3) 2.5 (2.0–3.1) 0.91
Pre-LT number of tumors (IQR) 1 (1–2) 1 (1–2) 1 (1–2) 1 (1–2) 0.08
Pre-LT serum AFP, ng/mL (IQR) 14 (6–48) 13 (5–41) 10 (5–36) 18 (8–73) 0.03
Milan-in at LT (%) 325 (86.7) 110 (90.9) 100 (89.3) 115 (81.0) 0.04
Explant size of the largest tumor, cm (IQR) 2.1 (1.3–3.0) 2.0 (0.9–3.0) 2.5 (1.8–3.3) 2.2 (1.2–3.2) 0.01
Explant number of tumors (IQR) 2 (1–3) 1 (1–2) 1 (0–1) 2 (1–4) 0.001
Microvascular invasion (%) 86 (22.9) 14 (11.6) 32 (28.6) 40 (28.2) 0.001
Macrovascular invasion (%) 17 (4.5) 1 (0.8) 6 (5.4) 10 (7.0) 0.05
Tumor differentiation (%) 0.30
 No viable tumor 62 (16.5) 25 (20.7) 15 (13.4) 22 (15.5)
 Well 61 (16.3) 22 (18.2) 21 (18.8) 18 (12.7)
 Moderate 213 (56.8) 62 (51.2) 61 (54.5) 90 (63.4)
 Poor 39 (10.4) 12 (9.9) 15 (13.4) 12 (8.5)
Overall SVR (%) 150 (40.0) 113 (93.4) 37 (33.0) 0 (0) <0.001
Time from antiviral to LT, y (IQR) 0.7 (0.1–1.0) b 0.2 (0.0–0.7) 0.8 (1.0–1.1) <0.001
aAmong 327 patients.
bAmong 233 patients.
AFP, alpha-fetoprotein; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; SVR, sustained virological response.

HCC Recurrence: Pretransplant Antiviral Therapy

During the follow-up, 65 patients had HCC recurrence: 8 (6.6%) in the pre-LT DAA group, 17 (15.2%) in the pre-LT IFN group, and 40 (28.2%) in the antiviral naïve group (P < 0.001). The 1-, 3- and 5-year HCC recurrence-free survival was 96.7%, 93.4%, 93.4% for pre-LT DAA; 92.0% versus 85.7% versus 84.8% for pre-LT IFN; and 88.7% versus 75.4% versus 73.9% for antiviral naïve groups, respectively (P < 0.001). Figure 3A shows the cumulative incidence of HCC recurrence by study groups.

FIGURE 3.
FIGURE 3.:
A, Probabilities of HCC recurrence in patients with HCC and HCV treated with pre-LT DAA, pre-LT IFN, and those who were antiviral naïve. B, Cumulative incidence of postliver transplantation HCC recurrence in patients with HCV treated with SVR induced by DAA or IFN before liver transplantation. CI, confidence interval; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IFN, interferon; LT, liver transplantation; SVR, sustained virological response.

A multivariable regression model predicting the hazard of HCC relapse was created (Table S4, SDC, http://links.lww.com/TP/B824). The use of pre-LT DAA was not associated with the risk of HCC recurrence (HR = 0.44 [95% CI, 0.19-1.00]) compared with those patients who were antiviral naïve at LT. The use of IFN therapies was associated with the risk of HCC recurrence (HR = 0.53 [95% CI, 0.30-0.95]) when comparing with antiviral naïve patients. Other factors associated with HCC recurrence were tumor size, number of lesions in the explant, and the presence of microvascular invasion. There was no difference in the results after stratifying for centers or effect modifications caused by tumor size, number of lesions, vascular invasion, serum AFP, and tumor differentiation.

Subgroup Analysis: SVR and Pre-LT DAA Versus Pre-LT IFN

Among the patients treated with pre-LT DAA, 113 (93.4%) achieved SVR, whereas in the pre-LT IFN group, 37 (33.0%) patients had achieved SVR. Tumor recurrence after LT occurred in 8 of 113 (7.1%) among pre-LT DAA-SVR patients and in 3 of 37 (8.1%) pre-LT IFN-SVR patients, P = 0.83. Figure 3B shows the HCC recurrence probabilities among patients with SVR treated with pre-LT DAA or pre-LT IFN.

Posttransplant Antiviral Therapy

Characteristics of Patients

Of the patients who were antiviral naïve at the time of LT, 500 (77.9%) were treated after LT: 395 (45.1% of total cohort) with DAA and 105 (12.0% of total cohort) with IFN. Table 3 summarizes the baseline characteristics of the patients treated with antiviral after LT. The timing of treatment was 2.0 (IQR, 1.1–3.9) years after LT for the post-LT DAA group and 2.1 (IQR, 2.1–3.2) years for the post-LT IFN group, P = 0.88. The median follow-up post-LT was 4.5 (IQR, 3.0–7.1) years for the post-LT DAA, 7.8 (IQR, 4.0–9.4) for the post-LT IFN, and 2.7 (IQR, 1.3–5.7) years for the treatment naïve group, P < 0.001. The tumor burden was similar between patients treated with post-LT DAA and IFN. Patients in the treatment naïve group had a slightly higher incidence of vascular invasion in their explants.

TABLE 3. - Characteristics of patients with HCV and HCC who underwent liver transplantation according to the type of antiviral treatment received after liver transplantation
Variable Overall
n = 642
HCV treatment
Post-LT DAA
n = 395
Post-LT IFN
n = 105
Naïve
n = 142
P
Sex, male (%) 534 (83.2) 330 (83.5) 88 (83.8) 116 (81.7) 0.86
Age at transplant (IQR) 57.0 (53.1–61.2) 57.5 (53.6–61.3) 54.7 (51.3–58.8) 57.3 (53.4–61.7) 0.01
Calculated MELD at transplant (IQR) 11.0 (8.7–14.0) 11.0 (8.9–14.6) 10.6 (8.7–13.5) 11.1 (8.7–14.0) 0.58
HCV genotype a (%) 0.05
 1 431 (69.7) 285 (72.5) 57 (55.9) 89 (72.4)
 2 18 (2.9) 11 (2.8) 5 (4.9) 2 (1.6)
 3 133 (21.5) 75 (19.1) 33 (32.4) 25 (20.3)
 4 30 (4.9) 20 (5.1) 6 (5.9) 4 (3.3)
 5 1 (0.2) 0 (0) 0 (0) 1 (0.8)
 6 5 (0.8) 2 (0.5) 1 (1.0) 2 (1.6)
Pre-LT locoregional therapy (%) 476 (74.1) 306 (77.5) 70 (66.7) 100 (70.4) 0.04
Pre-LT size of the largest tumor, cm (IQR) 2.5 (2.0–3.1) 2.5 (2.0–3.2) 2.5 (1.9–3.1) 2.5 (2.0–3.1) 0.11
Pre-LT number of tumors (IQR) 1 (1–2) 1 (1–2) 1 (1–2) 1 (1–2) 0.87
Pre-LT serum AFP, ng/mL (IQR) 16 (7–50) 16 (7–48) 17 (6–48) 18 (8–73) 0.49
Milan-in at LT (%) 530 (82.6) 327 (82.8) 88 (83.8) 115 (81.0) 0.83
Explant size of the largest tumor, cm (IQR) 2.2 (1.0–3.2) 2.1 (1.0–3.0) 2.3 (1.4–3.5) 2.2 (1.2–3.2) 0.42
Explant number of tumors (IQR) 1 (1–3) 1 (1–3) 1 (1–3) 2 (1–4) 0.01
Microvascular invasion (%) 132 (20.6) 74 (18.7) 18 (17.1) 40 (28.2) 0.04
Macrovascular invasion (%) 21 (3.3) 9 (2.3) 2 (1.9) 10 (7.0) 0.02
Tumor differentiation (%) 0.07
 No viable tumor 117 (18.2) 77 (19.5) 18 (17.1) 22 (15.5)
 Well 129 (20.1) 82 (20.8) 29 (27.6) 18 (12.7)
 Moderate 353 (55.0) 212 (53.7) 51 (48.6) 90 (63.4)
 Poor 43 (6.7) 24 (6.1) 7 (6.7) 12 (8.5)
Time between LT and antiviral, y (IQR) 2.0 (1.2–3.7) 2.0 (1.1–3.9) 2.2 (1.4–3.3) 0.83
Overall SVR (%) 452 (70.4) 381 (96.5) 71 (67.6) 0 (0) <0.001
Time from LT to antiviral, y (IQR) 2.0 (1.1–43.2) b 2.0 (1.1–3.9) 2.1 (1.4–3.2) 0.88
aAmong 618 patients.
bAmong 500 patients.
AFP, alpha-fetoprotein; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; SVR, sustained virological response.

HCC Recurrence: Posttransplant Antiviral Therapy

Tumor recurrence was diagnosed in 25 (6.3%) post-LT DAA patients, 12 (11.4%) post-LT IFN patients, and 40 (28.2%) patients in the treatment naïve group. The crude HCC recurrence incidence rate was 2.6 (95% CI, 1.5-4.5) recurrences per 100 person-year among post-LT DAA patients, 2.8 (95% CI 1.4-5.6) among post-LT IFN patients, and 3.3 (95% CI, 2.6-4.3) recurrences per 100 person-year among patients who did not receive antivirals, P = 0.04 (Figure 4A).

FIGURE 4.
FIGURE 4.:
Cumulative incidence of HCC recurrence according timing of treatment and SVR status. A, Cumulative incidence of HCC recurrence according to different antiviral therapies after liver transplantation. B, Cumulative incidence of postliver transplantation HCC recurrence in patients with HCV treated with SVR induced by DAA or IFN after liver transplantation. CI, confidence interval; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IFN, interferon; LT, liver transplantation; SVR, sustained virological response.

In a multivariable regression model, the use of post-LT DAA was not associated with the risk of HCC recurrence (HR = 0.62 [95% CI, 0.33-1.16]) compared with those patients who were antiviral naïve. The use of IFN-based therapies after LT was not associated with the risk of HCC recurrence (HR = 1.72 [95% CI, 0.77-3.85]) when compared with antiviral naïve patients. Risk factors for HCC recurrence were tumor size and number of lesions on the explant and the presence of microvascular invasion. Table S5 (SDC, http://links.lww.com/TP/B824) summarizes the complete results of this analysis.

Sensitivity Analysis: Antiviral Treatment Within 2 Years From LT

We assessed the recurrence incidence among patients who were treated with antivirals up to 2 years from LT. We identified 199 patients in this subgroup: 156 (78.4%) were treated with DAA and 43 (22.6%) were treated with IFN. Among DAA patients, 12 (7.7%) had HCC recurrence, and among IFN patients, 4 (9.3%) had tumor relapse (P = 0.73). The crude incidence of HCC recurrence was 3.9 (95% CI, 2.2-6.9) for DAA patients and 2.1 (95% CI, 0.8-5.5) recurrences per 100 person-year for IFN patients (P = 0.79).

Subgroup Analysis: SVR and Post-LT DAA Versus Post-LT IFN

Among the patients treated with DAA after LT, 381 (96.5%) achieved SVR. Among IFN patients, 71 (67.6%) achieved SVR. The tumor recurrence rate among these patients was 11 of 381 (2.9%) in those treated with DAA post-LT and 5 of 71 (7.0%) among those treated with IFN post-LT (P = 0.08). Figure 4B shows the cumulative incidence of HCC recurrence between these 2 subgroups.

Patterns of HCC Recurrence

Among patients antiviral naïve, the median time to HCC recurrence was 1.1 (IQR, 0.7–2.0) years. In comparison with pre-LT DAA (median 0.9 [IQR, 0.3–1.6] y) and pre-LT IFN (median 0.9 [IQR, 0.5–1.5] y), there were no significative differences (P = 0.33). With regard to the post-LT DAA, the median time-to-recurrence was 1.8 (IQR, 1.4–2.5) years and in post-LT IFN, 3.0 (IQR, 1.5–3.6) years. Again, no difference between the 3 study groups was seen (P = 0.49).

In the antiviral naïve group, the recurrence was hepatic in 17 of 40 (42.5%) patients and 23 of 40 (57.5%) patients had extrahepatic recurrence. In the pre-LT DAA group, tumor recurrence location was hepatic in 2 of 8 (25.0%) patients and extrahepatic in 6 of 8 (75.0%) patients. In the pre-LT IFN group, hepatic recurrence occurred in 5 of 17 (29.4%) and extrahepatic in 12 of 17 (70.6%). There was no significant difference between the location of recurrence between patients antiviral naïve versus pre-LT DAA versus pre-LT IFN (P = 0.49). In the post-LT DAA group, the recurrence was hepatic in 14 of 25 (56.0%) and extrahepatic in 11 of 25 (44.0%) patients. In the post-LT IFN group, hepatic recurrence was diagnosed in 4 of 12 (33.3%) of patients, whereas 8 of 12 (66.7%) of patients had extrahepatic recurrence. No difference was seen between naïve patients, post-LT DAA, and post-LT IFN (P = 0.37).

DISCUSSION

This study has shown that the incidence of HCC recurrence is not different in DAA-treated patients compared with those treated with IFN and those who are treatment naïve. After adjustment for patient and tumor characteristics, we did not associate the use of DAA with HCC recurrence. The large sample size, the use of a single highly effective HCC therapy for all patients, and the availability of precise pathological staging make this evidence more robust. Accounting for competing risks between HCC recurrence and death not related to HCC provided more specific hazard estimations. We included centers from North America and Europe, improving the external validity of the results.

The initial success of DAAs was somewhat restrained after the publication of articles on their use in patients with HCC. Reig et al11 published a series of 58 patients with treated-HCC (ablation, resection, and transarterial chemotherapy) who underwent DAA treatment. They reported a recurrence rate of 27.6% after a median follow-up of 5.7 months. Conti et al12 studied 56 patients with HCC treated with DAA and described 17 (30.3%) recurrences. Both studies had small numbers and neither accounted for important recurrence risk factors such as tumoral morphology and vascular invasion. Moreover, the lack of comparative groups impairs causal conclusions in these studies. Data from the France REcherche Nord & sud Sida-vih Hépatites cohort showed that among 189 DAA-treated patients, the recurrence rate was not different from the 78 IFN-treated patients.14 Singal et al16 analyzed HCV-HCC patients who underwent different treatment strategies for HCC (except LT). They demonstrated that DAA therapy was not associated with the risk of HCC recurrence. Mashiba et al26 identified no impact of DAA therapies on HCC recurrence in a multicenter Japanese cohort. However, these studies did not specify the type of HCC treatment patients underwent.

We accounted for well-known risk factors for HCC recurrence, including pathology data. Our global recurrence rate (11%) is in accordance with the literature for an HCV-infected population.27 Each center defined its’ own policy about HCC recurrence surveillance protocols. This might represent an inherent bias of a retrospective study. On the other hand, our recurrence rate represents real-world data from LT centers in North America and Europe. We demonstrated that the tumor burden and the presence of microvascular invasion are predictors of HCC recurrence, which is in accordance with seminal studies in this field.28-30 Interestingly, serum AFP was not a predictor for HCC recurrence in our cohort. This could be due to a selection bias given that some participant centers apply serum AFP as part of their LT selection criteria. Of note, 75% of the patients in this cohort had a serum AFP <50 ng/mL.

In the “pre-LT treated” cohort, the incidence of HCC recurrence was lower among patients treated with DAA. However, the protective effect of pre-LT DAA was not statistically significant (P = 0.051). This finding could be related to a beta error. The majority of patients treated before LT finished their antiviral treatment within 1 year before LT. Among pre-LT DAA, nearly 80% of patients had viable HCC on their explant, suggesting that these patients were treated with DAA, while they had active HCC. Nevertheless, pre-LT DAA patients were more likely to receive locoregional therapies, perhaps because of better liver function. In accordance with previous studies, pre-LT locoregional therapies did not show any impact on post-LT tumor recurrence.31,32 Patients who received DAA before LT have lower incidence of vascular invasion in their explants. Unfortunately, at this point, we cannot correlate the use of pre-LT DAA and less aggressive HCC biology or tumoral progression during waiting time. This finding should be the aim of further investigation under specific designed studies. In the post-LT analysis, most patients were treated with antivirals within 2 years from LT. This represents the time frame of higher incidence for HCC recurrence.33 The unadjusted incidence of recurrence among post-LT DAA was lower than the other groups. However, after multivariable analysis, the use of post-LT DAA was not related to recurrence. Patients treated with IFN had higher mortality in the ITT analysis without a higher incidence of HCC recurrence. This likely represents deaths not related to HCC, but probably, due to end-stage liver disease. We identified a 28% recurrence rate on patients who did not receive antivirals. These patients had more aggressive HCC signature presented as higher tumoral burden and higher frequency of vascular invasion.

We showed that majority of recurrence were diagnosed within 2 years from LT. The most common site of recurrence was extrahepatic. This has been reported previously.34 There was no difference in patterns of recurrence between antiviral groups. Although not statistically significant, the time-to-recurrence was shorter among post-LT DAA patients: median of 1.8 years in post-LT DAA and 3.0 years in the post-LT IFN group. This difference might be a result of the shorter follow-up time among patients treated with post-LT DAA. Further studies will be needed to investigate the impact of post-LT DAA on time-to-recurrence. There was no difference between DAA-induced SVR or IFN-induced SVR in the pre- or posttransplantation setting. Although the benefit of SVR after HCC treatment has been reported previously,8-10 the potential benefit of DAA-induced SVR (if any) should be the aim of further investigation, ideally by prospective trials.

The retrospective design is responsible for the lack of clinically important variables such as Child-Pugh score or liver disease status during the follow-up. The decision to treat or not certain patients could be influenced by factors not taken into account in our analysis. We believe, however, that the lack of some specific information does not invalidate the results of this study. Most of the IFN patients were treated before 2013 and therefore had no access to DAA therapy. The very low number of events among patients treated with DAA and IFN made not possible to perform any multivariable analysis between these 2 groups. For this reason, we could not include SVR or the time span between LT and the antiviral (or vice versa) in the multivariable models. In the same way, direct comparisons between DAA-SVR with IFN-SVR were limited by the small numbers. We did not account for any specific variations in the DAA regimens. However, describing in detail DAA regimens in transplanted patients was beyond the scope of this study. Given the multicenter involvement, there was no standardization with regard to the decision-making of antiviral treatments, the HCC recurrence surveillance protocols, or the immunosuppression regimens used post-LT. These are biases almost impossible to be ruled out; however, we believe our center-effect stratification has contributed to the analysis. Finally, the follow-up of DAA patients was shorter than the follow-up in the other groups. This is a prevailing limitation in other similar studies26,35 and is not remarkable given the relatively recent addition of DAA to our HCV treatment armamentarium. We believe this difference does not jeopardize our results given that >75% of DAA patients were followed for >2 years, which is enough to assess most HCC recurrences after LT.36

In conclusion, we demonstrated that DAA is not associated with an increased risk of death or HCC recurrence in HCV-HCC patients. The recurrence patterns were not different among patients treated with DAA, IFN, and those treatment naïve patients. Among patients who achieved SVR after LT, the incidence of HCC recurrence was similar among patients treated with DAA or IFN. These data suggest that there is no oncological contraindication to treating HCV-HCC patients with DAA before or after LT.

ACKNOWLEDGMENTS

The authors thank Eliana Agudelo PA-C for her assistance with data collection.

REFERENCES

1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018; 391:1301–1314
2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359–E386
3. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012; 142:1264–1273.e1
4. Maan R, van Tilborg M, Deterding K, et al. Safety and effectiveness of direct-acting antiviral agents for treatment of patients with chronic hepatitis C virus infection and cirrhosis. Clin Gastroenterol Hepatol. 2016; 14:1821–1830.e6
5. Younossi ZM, Stepanova M, Feld J, et al. Sofosbuvir and velpatasvir combination improves patient-reported outcomes for patients with HCV infection, without or with compensated or decompensated cirrhosis. Clin Gastroenterol Hepatol. 2017; 15:421–430.e426
6. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018; 69:461–511
7. Adam R, Karam V, Delvart V, et al.; All Contributing Centers (www.eltr.org); European Liver and Intestine Transplant Association (ELITA). Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol. 2012; 57:675–688
8. 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
9. Calvaruso V, Cabibbo G, Cacciola I, et al.; Rete Sicilia Selezione Terapia–HCV (RESIST-HCV). Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology. 2018; 155:411–421.e4
10. Hsu CS, Chao YC, Lin HH, et al. Systematic review: impact of interferon-based therapy on HCV-related hepatocellular carcinoma. Sci Rep. 2015; 5:9954
11. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016; 65:719–726
12. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016; 65:727–733
13. Nagata H, Nakagawa M, Asahina Y, et al.; Ochanomizu Liver Conference Study Group. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol. 2017; 67:933–939
14. ANRS Collaborative Study Group on Hepatocellular Carcinoma. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J Hepatol. 2016; 65:734–740
15. Huang AC, Mehta N, Dodge JL, et al. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology. 2018; 68:449–461
16. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology. 2019; 156:1683–1692.e1
17. 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
18. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017; 14:203–217
19. Bielen R, Moreno C, Van Vlierberghe H, et al. The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C-infected patients treated with direct-acting antivirals with and without pegylated interferon: a Belgian experience. J Viral Hepat. 2017; 24:976–981
20. Yang JD, Aqel BA, Pungpapong S, et al. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol. 2016; 65:859–860
21. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011; 53:1020–1022
22. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954; 7:462–503
23. von Elm E, Altman DG, Egger M, et al.; STROBE Initiative. The strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg. 2014; 12:1495–1499
24. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012; 308:2584–2593
25. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. JASA. 1999; 94:496–509
26. Mashiba T, Joko K, Kurosaki M, et al. Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? A multicenter study by the Japanese Red Cross Hospital Liver Study Group. PLoS One. 2018; 13:e0194704
27. Dumitra S, Alabbad SI, Barkun JS, et al. Hepatitis C infection and hepatocellular carcinoma in liver transplantation: a 20-year experience. HPB (Oxford). 2013; 15:724–731
28. Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007; 7:2587–2596
29. Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology. 2016; 64:2077–2088
30. Toso C, Trotter J, Wei A, et al. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma. Liver Transpl. 2008; 14:1107–1115
31. Kulik L, Heimbach JK, Zaiem F, et al. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: a systematic review and meta-analysis. Hepatology. 2018; 67:381–400
32. Agopian VG, Harlander-Locke MP, Ruiz RM, et al. Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within Milan criteria undergoing liver transplantation: analysis of 3601 patients from the US multicenter HCC transplant consortium. Ann Surg. 2017; 266:525–535
33. Mehta N, Heimbach J, Harnois DM, et al. Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol. 2017; 3:493–500
34. Pecchi A, Besutti G, De Santis M, et al. Post-transplantation hepatocellular carcinoma recurrence: patterns and relation between vascularity and differentiation degree. World J Hepatol. 2015; 7:276–284
35. Nahon P, Layese R, Bourcier V, et al.; ANRS CO12 CirVir Group. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs. Gastroenterology. 2018; 155:1436–1450.e6
36. Sapisochin G, Goldaracena N, Astete S, et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series. Ann Surg Oncol. 2015; 22:2286–2294

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