Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma
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"In conclusion, we did not find any evidence that DAA treatment increases the risk of recurrence of HCC in DAA-treated patients compared with untreated patients. In another study, we have also observed a decreased risk of HCC over time in cirrhotic or non cirrhotic patients achieving SVR after DAAs .. The prospective follow-up of a large number of patients included in three distinct cohorts of patients reflecting various clinical profiles ensures the quality of our analyses and the confidence in our conclusions." this new study questions the 3 immediately below...
from Jules: this study is a big deal & I think was conducted to address the study at EASL that found HCC risk high in patients achieving HCC with DAAs who had cirrhosis & had HCC previously, the study found a high rate & a rate much higher than those who achieved SVR but did not have HCC prior to DAA SVR, and then a study was published right after EASL without a comparator arm but also find similarly high SVR rates in the same group of patients, with HCC prior to SVR with DAAs. Then a Japanese analysis was published as a letter to the editor that compared patients with cirrhosis with IFN based therapy SVR to DAAs SVR and found higher HCC rates for those using IFN-free therapy, suggesting that IFN may be protective, also the published study without comparator arm discusses and suggests that IFN may be protective:
Changes in patient backgrounds may increase the incidence of HCC after SVR in the era of IFN-free therapy for HCV - Letter to the Editor - (05/18/16)
EASL: Development of Hepatocellular Carcinoma in HCV Cirrhotic Patients Treated with Direct Acting Antivirals - (04/25/16)
Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution - (04/27/16)
 Clinical outcomes in HCV-infected patients treated with direct acting antivirals - 18-month post-treatment
follow-up in the French ANRS CO22 HEPATHER Cohort
Article in Press
Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma
The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CIRVIR and CO23 CUPILT cohorts)
Jnl of Hepatology June 2016
Pr. Stanislas Pol, MD, PhD. The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CIRVIR and CO23 CUPILT cohorts)
Background and aims
Sustained virological response following antiviral interferon- based treatment of chronic hepatitis C is associated with decreased long-term risk of hepatocellular carcinoma (HCC) in advanced liver fibrosis. An unexpected high rate of HCC recurrence following antiviral treatment using direct acting antiviral (DAA) has been recently reported.
We analyzed data individually from three French prospective multicenter ANRS cohorts including more than 6,000 patients treated with DAA and we focused on HCC patients who underwent curative procedures before DAA treatment. The aim was to assess the rates of HCC recurrence in these patients according to antiviral treatment regimen.
In the ANRS CO22 HEPATHER cohort, 267 patients with CHC who were previously treated for HCC were analyzed, among whom 189 received DAA and 78 did not. The rates of recurrence were 0.73/100 and 0.66/100 person-months, respectively. In the ANRS CO12 CIRVIR cohort, 79 cirrhotic patients in whom HCC was diagnosed and treated, 13 received DAA and 66 did not. The rates of recurrence were 1.11/100 and 1.73/100 person-months, respectively. In the ANRS CO23 CUPILT Cohort, 314 liver transplant recipients for HCC who were subsequently treated with DAA were analyzed. Seven HCC recurrences were reported after a median time of 70.3 months after liver transplantation. The rate of recurrence was 2.2%.
In three distinct prospective cohorts, we did not observe an increased risk of HCC recurrence after DAA treatment, notably in patients who underwent curative HCC treatment including liver transplantation.
Since an unexpected high rate of hepatocellular carcinoma (HCC) recurrence after direct acting antiviral (DAA) treatment has been suggested in a retrospective study, we analyzed data from three French prospective multicenter ANRS cohorts of > 6,000 DAA treated patients who underwent curative HCC therapies.
We did not observe an increased risk of HCC recurrence after DAA treatment: the rates of recurrence were similar in treated and untreated patients (0.73/100 and 0.66/100 person-months in in the ANRS CO22 HEPATHER cohort including 189 DAA+ and 78 DAA- and 1.11/100 in 13 DAA+ and 1.73/100 person-months in 66 DAA- in the ANRS CO12 CIRVIR cohort), respectively. Finally, in the ANRS CO23 CUPILT Cohort, HCC recurred in only 7 among 314 (2.2%) liver transplant recipients for HCC subsequently treated after 70 months after liver transplantation.
Currently, high rates of sustained virological response (SVR) are achieved in patients with chronic hepatitis C treated with direct-acting antivirals (DAAs) [, , ].
Viral eradication is associated with a reduced risk of liver complications, including the occurrence of HCC, as reported in a recent meta-analysis: Relative Risk (RR) = 0.24 in all stages of fibrosis; RR = 0.23 in advanced liver disease . These results were only supported by studies with IFN-based regimens.
Surprisingly, a high rate of tumor recurrence has been recently reported after antiviral treatment of chronic hepatitis C using DAAs in 16 of 58 patients (28%) with apparent complete remission after HCC treatment . Most of these patients had previous surgical resection or radio-frequency ablation and had favorable prognostic factors with an expected low rate of HCC recurrence (<4-5%) . Another study of 59 patients with HCC remission at start of DAA therapy reported a 29% rate of early HCC recurrence within 6 months of therapy . Similar data has not been suggested by pivotal controlled trials performed in the population of patients with cirrhosis, however patients with a history of HCC had been systematically excluded.
This data prompted us to assess the risk of HCC recurrence in three distinct prospective cohorts of the French ANRS (France REcherche Nord&sud Sida-vih Hépatites) agency including HCV-infected patients with or without cirrhosis who received DAA therapy. The current analyses are focused on HCC patients who underwent curative management for their liver tumor based on hepatic resection, percutaneous ablation or liver transplantation before starting DAA therapy. The rates of HCC recurrence were assessed in this population according to antiviral therapy.
PATIENTS AND METHODS
The present work analyzed three distinct prospective cohorts, sponsored and funded by the ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), namely, ANRS CO22 HEPATHER, ANRS CO12 CIRVIR, ANRS CO23 CUPILT.
ANRS CO22 HEPATHER cohort
The ANRS CO22 HEPATHER cohort << Therapeutic options for hepatitis B and C: a French cohort >> is a multicentre observational cohort which aims to include 15 000 HCV- and 10 000 HBV-infected patients, to quantify the clinical efficacy and safety of new hepatitis treatments in real-life, and to identify, at the patient level, which treatment will most likely improve overall health (ClinicalTrials.gov, NCT01953458). HCV-positive patients are defined as patients with positive HCV-RNA or positive anti-HCV antibodies. Each patient gave written informed consent before enrollment and the protocol was conducted in accordance with the Declaration of Helsinki and French law for biomedical research and was approved by the "CPP Ile de France 3" Ethics Committee (Paris, France) and the French Regulatory Authority (ANSM). By December 31st, 2015, 14,379 participants with past or active chronic hepatitis C infection had been recruited; among whom 5,458 had begun a Direct Acting Agent (DAA) therapy from entry.We selected all participants with chronic active hepatitis C and a history of treated hepatocellular carcinoma (HCC) prior to inclusion (n=307), and we excluded patients with progressive or active recurrence of HCC upon inclusion (n=40).
ANRS CO12 CIRVIR cohort
The ANRS CO12 CirVir cohort is a multicentre observational cohort which aims to characterize the incidence of complications occurring in biopsy-proven compensated cirrhosis and to identify the associated risk factors using competing risks analysis . Patients were recruited in 35 French clinical centres between 2006 and 2012. Inclusion criteria were: histologically proven cirrhosis due to HCV or HBV; Child-Pugh A; and no previous hepatic complications . Patients were seen by physicians every 6 months, and the usual clinical and biological data were recorded. Examination by Doppler US was performed every 6 months. When HCC diagnosis was established, treatment was determined using a multidisciplinary approach according to AASLD guidelines for HCC.[, ]
All events occurring during follow-up, liver-related or not, were recorded based on information obtained from patient medical files from each centre. Likely cause(s) of death were established.
A total of 1,822 cirrhotic patients were included. Among them, 151 were subsequently excluded from analysis after reviewing individual data either due to non-compliance with inclusion criteria (n=142) or consent withdrawal (n=9). Consequently, 1,671 patients among whom 1,354 had HCV-related compensated cirrhosis, were selected for further analysis. On January 5, 2016, after a median follow-up of 58.6 [36.5-79.1] months, a first hepatic focal lesion was observed in 409 patients (30.2%) with a 5-year cumulated incidence (CumI) estimated at 32.3%. Following a diagnostic procedure, more than half of these focal liver lesions remained indeterminate or were considered benign (n=214, 52.3%). A definite diagnosis of primary liver cancer (PLC) was established in the remaining 195 patients: HCC (n=189) and intra-hepatic cholangiocarcinoma (n=6). HCC 5-yr CumI was 13.9%.
ANRS CO23 CUPILT cohort
The ANRS C023 "Compassionate use of Protease Inhibitors in viral C Liver Transplantation" (CUPILT) study is a multicentre, cohort study implemented in 24 French and one Belgian liver transplant (LT) centres (ClinicalTrials.gov number NCT01944527). To be enrolled in this cohort, patients must comply with the following associated criteria, which include: (1) having received a liver transplant for an HCV infection, (2) having experienced an HCV recurrence in any stage of fibrosis, (3) having been treated with second-generation DAAs. All patients provided their informed consent before inclusion.
Among the 699 liver transplant recipients enrolled between October 2013 and December 2015, 330 (47%) received LT for HCC. We excluded patients receiving Peg-interferon concurrently with their DAA regimen (n=12) and those presenting with active HCC recurrence at baseline (n=4). Finally, 314 patients were included in the analysis.
The flow charts of the 3 cohorts are depicted in Fig. 1 and the main patient characteristics are summarized in Table 1.
ANRS CO22 HEPATHER cohort
In the ANRS CO22 HEPATHER cohort, our analysis focused on 267 patients with a history of treated hepatocellular carcinoma (HCC) prior to inclusion among whom 189 received DAA from inclusion (DAA group), 78 did not receive DAA (untreated group). Overall, 147 (78%) patients from the DAA group were male versus 57 (73%, P=0.4107) in the untreated group. In comparison, patients from the DAA group were younger (mean (+/- SD) age of 62 (+/-9) years versus (vs) 66 (+/- 10) years, P=0.0047) and prior HCV interferon-based therapy was more frequent (80% vs 69%, P=0.0529). Severe fibrosis or cirrhosis was also more frequent in the DAA group (78% vs 63%, P=0.0148). No other difference was noticed between the two groups in regards to time between HCC discovery and inclusion (Median 1.8 years, Interquartile Range (IQR) 0.7-4.4 years), time between last assessment of HCC and inclusion (Median 1.1 (IQR 0.4-3.2) years), duration of HCV infection (Median 15.3 (IQR 9.2-20.1) years) or HCV Genotype (65% genotype 1).
Survival time in patients treated with DAA was considered as time-dependent to distinguish between the time from inclusion in the cohort to therapy initiation (untreated period) and the time from therapy initiation to end of follow-up (treated period). The median follow-up was 1.4 months before DAA initiation, 20.2 months after DAA initiation and 26.1 months for untreated patients. Overall, 24 recurrences of HCC were reported in 3,292 treated person-months (at a rate of 0.73/100 person-months), while 16 recurrences of HCC were reported in 2,438 untreated person-months (at a rate of 0.66/100 person-months, P=0.8756, Fig. 2). The estimated hazard ratio (HR) for time-dependent DAA treatment was 1.21 (95%CI (0.62-2.34), P=0.5782). Multivariate adjustments on age, past treatment experience and severe fibrosis or cirrhosis did not modify the findings (multivariate adjusted HR for time-dependent DAA treatment (1.04 (95%CI (0.53-2.07), P=0.9060). We did not find an increase in HCC recurrence rate during the first 3 months of the treated period (which corresponds to active treatment intake in most patients) compared with the period following the first 3 months (1.27/100 person-months vs 0.62/100 person-months, P=0.1831). Recurrences of HCC occurred in 5 patients who received sofosbuvir+peginterferon±ribavirin (at a rate of 1.52/100 person-months) and in 19 patients who received other combination therapies (at a rate of 0.64/100 person-months, P=0.1715), suggesting that interferon did not modify the risk of early HCC recurrence.
ANRS CO12 CIRVIR cohort
In the ANRS CO12 CIRVIR cohort, 79 HCC patients were considered to be in remission at least 3 months following the implementation of at least one curative procedure. Overall, most of these patients met Milan criteria (Table 2). Thirteen patients subsequently received a DAAs-based regimen after anti-tumoral treatment. One patient (7.7%) experienced HCC recurrence after 37.1 months while 31 recurrences occurred among the remaining 66 patients (47.0%) who did not received DAAs.
Overall, 31 recurrences occurred in 1789 untreated person-months (at a rate of 1.73/100 person-months) and 1 recurrence was reported in 90 treated person-months (at a rate of 1.11/100 person-months, P=0.748). The hazard ratio for time-dependent DAA treatment intake was 0.41 (95% CI [0.05-3.08], P=0.386). The estimation of the hazard ratio was not modified by adjustment for age at the first HCC diagnosis (0.40, 95% CI [0.05-3.03]), P=0.377).
ANRS CO23 CUPILT cohort
In the ANRS CO23 CUPILT cohort, 314 liver transplant recipients for HCC were treated with DAA. The mean time between LT and the initiation of DAA was 67 ± 60 months. The planned durations of treatment were as follows: 12 weeks, n= 109 (35%); 24 weeks, n=198 (63.7%); 16 weeks, n=3 (1.0%) and 26 weeks, n=1 (0.3%). Among the 248 patients who reached 12 weeks of follow-up, the overall SVR12 rate was 96.8%. A recurrence of HCC was observed in seven patients (2.2%) (mean age 58.0 +/- 8.4 years) within mean time after LT of 70 ± 64 months, 7 ± 3 months, 21 ± 14 weeks following the introduction of DAAs and after obtaining viral clearance, respectively. Five of the seven patients (71%) died 58 ± 47 months after LT.
The characteristics of the seven patients are detailed in Table 3. At inclusion, six of the seven patients (86%) met Milan criteria. Five patients displayed factors predictive of a recurrence based on histological criteria in the native liver. However, microvascular invasion in the native liver was present in two (28%) of the seven patients, and in two others, without vascular invasion a large number of active nodules was observed (patient 2, n=4; patient 5, n=8).
Moreover, we observed that two patients (patients 4 and 7) experienced a first episode of recurrence when they were considered to be in complete remission after LT and before the introduction of DAA.
These three prospective multicentre cohorts, dealing with different patient profiles including cirrhotic and non cirrhotic patients and liver transplant recipients, do not support any evidence of an increased risk of HCC recurrence in patients treated with DAA.
The strength of this present work is the large size of patients treated with DAA and that each cohort contributes unique information that gives consistent results.
The HEPATHER, CirVir and CUPILT cohorts are all characterized by prospective rigorous multicenter protocol-driven systematic data collection and analysis of predefined outcomes. The HEPATHER cohort included a large number of patients treated with DAAs ensuring a high statistical power to identify an increased risk of events during treatment, while the analyses conducted in the CirVir cohort were performed in incidental cases of well-phenotyped HCC occurring during follow-up of patients, thus ensuring the unbiased record of tumors and their evolution after therapeutic management. The CUPILT cohort included only DAA-treated patients after liver transplantation among whom almost half were transplanted for HCC. The expected risk of recurrence following LT range from 8 to 20% within the first 2 years after LT .
Another strength of our work is our focus on patients previously treated for HCC using curative procedures (hepatic resection, percutaneous ablation or liver transplantation) as we excluded patients treated with chemoembolization. Indeed, the recent Spanish study suggesting an high risk of HCC recurrence have included patients with non curative therapies such as chemoembolization, characterized by high early recurrence rates .
With an annual rate of recurrence reaching 20% after resection or percutaneous ablation , it is tempting to speculate that incomplete treatment or mistaken initial staging of tumour burden might also introduce interpretation biases in those retrospective studies. This may lead to an erroneous attribution of DAAs being responsible for HCC recurrence. The prospective design of the cohorts allowed us to cautiously select patients according to tumoral response, in particular those who achieved complete remission after the implementation of a curative procedure and before the introduction of DAA.
Moreover, in 2 of these cohorts (HEPATHER and CIRVIR) we compared HCC patients who received DAA to those who did not. In both cohorts there was no evidence of an increased risk of HCC recurrence in treated compared with untreated patients. Similarly, in the CUPILT cohort which included treated patients only, the observed recurrence rate of 2.2% was lower than the expected rate according to previous studies with Interferon regimen.
DAAS are associated with a SVR in more than 90% of patients and SVR is a variable usually associated with a decreased risk of both HCC occurrence and HCC recurrence. What could explain the paradox of an increased risk of HCC? Authors hypothesized that the rapid control of inflammatory state could impact anti-tumoral immune control allowing for tumor clones emergence . The qualitative and quantitative immune alterations which are associated with chronic HCV infection may be restored in a time-dependent fashion  but persists an imbalance between different cytokines/chemokines which may decrease the regional immune control of tumoral clones [, ].
Overall, the analyses performed in these prospective cohorts did not underline a specific link between DAA treatments and the risk of HCC recurrence after the implementation of curative procedures including liver transplantation.
In conclusion, we did not find any evidence that DAA treatment increases the risk of recurrence of HCC in DAA-treated patients compared with untreated patients. In another study, we have also observed a decreased risk of HCC over time in cirrhotic or non cirrhotic patients achieving SVR after DAAs .
The prospective follow-up of a large number of patients included in three distinct cohorts of patients reflecting various clinical profiles ensures the quality of our analyses and the confidence in our conclusions.