Editorial

HCC After DAAs Requires More Study, but no Cause for Withheld Treatment

As we continue to see the success of direct-acting antiviral therapy in treating hepatitis C virus, we must be aware of any potential complications from the underlying liver disease after successful treatment, especially hepatocellular carcinoma.

In the pre-DAA era, studies showed a reduction of HCC occurrence in patients with HCV who attained SVR. In a 2012 study by Adriaan J. van der Meer, MD, and colleagues, the 10-year cumulative occurrence rate of HCC was just 5.1% in patients who met SVR, in contrast to 21.8% in those who failed interferon-based therapies. A pooled analysis by Rebecca L. Morgan, MPH, and colleagues, in 2013 showed a significant reduction in HCC post-SVR: 1.5% of SVR patients developed HCC vs. 6.2% of non-SVR. Yet, at both the International Liver Congress in 2016 and subsequently, studies have led us, rather unexpectedly, to question whether DAA therapy may affect a patient adversely with regard to the development of HCC both in patients with a history of HCC and in a de novo fashion.

ILC 2016 Data

In a Late Breaking presentation in Barcelona, we saw data on 344 patients with HCV-related Child-Pugh A/B cirrhosis, without active HCC. They were treated with a variety of DAAs, with or without ribavirin, and occurrence of HCC was monitored through 6 months.

At the end of the follow-up period, 7.6% of all patients were diagnosed with HCC with 29% (17/59) of those with previous treated HCC showing recurrence. In contrast, only 3.2% (9/285) of those without such a history presented with de novo HCC.

In a similar vein, a study by María Reig, MD, and her Barcelona colleagues looked at 58 patients with a history of HCC followed by treatment with DAAs. They showed that 16 patients (27.6%) had radiologic recurrence within a median 5.7 months of follow-up. In a commentary on Reig’s study, Ju Dong Yang, MD, and colleagues showed that patients on the waiting list for liver transplant for HCV-associated HCC who received pre-transplant DAA therapy trended toward a higher HCC recurrence (27.8%) vs. their untreated counterparts (9.5%). The authors of this study did mention that three of the five patients who recurred in the treated group had not achieved SVR.

In decompensated cirrhotics, Michelle Cheung, MD, MPH, FAAP, showed no signal for increased rates of HCC after DAA-induced SVR. The researchers followed more than 406 patients up to 15 months and saw a 4% occurrence of HCC in the first 6 months, whether treated or untreated. In those who achieved SVR24, there was a 5.4% rate of HCC as compared to 4.2% in the untreated arm. In those that failed DAA therapy, the rate of HCC was 11.2%.

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Other studies have provided reassurance that an increased risk of HCC recurrence does not exist after successful DAA therapy. An important ANRS publication from France evaluated three separate patient cohorts derived from large multicenter studies of cirrhotic patients, and found no evidence of a significant increase in HCC incidence in SVR patients relative to untreated comparator populations. Moreover, a recent study from the Italian Liver Cancer Group suggested a similar reduction in HCC recurrence after successful treatment with either interferon-based or DAA therapies.

Ira M. Jacobson

So while it has been theorized that a loss of intrahepatic immune surveillance could be a mechanism for HCC recurrence after DAAs, the data is insufficient to change our current treatment recommendations, which is to treat everyone.

Yet if we allow for even the possibility of a trend toward recurrence, with a putative causative mechanism underlying this possibility, the question must be asked: could there be an increased risk of de novo HCC in the immediate aftermath of SVR? After all, a certain percentage of cirrhotics already harbor tumor cells that are still clinically or radiologically undetectable.

Liver Meeting Data

At The Liver Meeting, we saw one study where incident HCC initially appeared to be more common after sofosbuvir-based DAA therapy, but after adjustment for baseline patient features the trend was negated. In another study from Italy, researchers followed more than 3,000 patients with F3 and F4 cirrhosis treated with DAAs. In a mean follow-up of 300 days, 41 participants developed HCC for an incidence of 1.64% persons per year, which is not excessive. In this study, SVR12 was associated with a 0.20 hazard ratio.

The most provocative discussion arising from this Italian study presented by Alfredo Alberti, MD, came from their report of an increased appearance of HCC with more than three nodules: 33.3% in those who achieved SVR; 53.8% in those who did not achieve SVR; and 28.6% in those still pending SVR. So we question now if DAAs are impacting the etiology of the HCC that is occurring de novo after treatment.

With all of these studies in mind, many are questioning why HCC arises after SVR and if we can predict its appearance. A study presented by James Crismale, MD, at the Liver Meeting showed varied characteristics of patients with post-SVR HCC: 12% had pre-treatment steatosis, 29% did not have cirrhosis and there was an association with non-white patients and albumin less than 3.5 g/dL. With these findings, the authors called for investigation into biomarkers of HCC risk after SVR.

Using genome-wide association study in a Japanese cohort developing HCC more than 1 year after SVR, another set of researchers showed a nearly two-fold risk of HCC with the TLL1 SNP rs17047200. They concluded that TLL1 may contribute to HCC development via hepatic fibrogenesis. Due to the increased risk associated with this, they suggest genetic testing for the TLL1 SNP could help implement personalized surveillance of HCC post-SVR. This is an area that calls for extensive additional research.

PAGE BREAK

Looking Ahead

Though the data is limited to these studies as we are just now seeing long-term implications of DAAs, the frequency of HCC recurrence after DAA therapy is still controversial. We require larger studies but the existing evidence does not support the withholding of antiviral therapy from patients with HCV even with a history of HCC.

With regard to de novo HCC post-SVR, there remains incontrovertible evidence for a major reduction in de novo HCC risk after SVR. There is no convincing evidence for a transient “spike” in de novo HCC post-SVR with DAAs, but the question of an alteration in the biology of de novo HCC after SVR requires further study.

Most experts agree that it remains critical to screen for HCC after SVR in cirrhotic patients even if cirrhosis appears to regress. For patients with a history of HCC, clinicians must exercise individual judgement with regard to an increased frequency of surveillance beyond the standard of semiannual imaging for a period of time after antiviral therapy in patients considered to be at particular risk of recurrence.

Ira M. Jacobson, MD

HCV Next

Co-Chief Medical Editor

As we continue to see the success of direct-acting antiviral therapy in treating hepatitis C virus, we must be aware of any potential complications from the underlying liver disease after successful treatment, especially hepatocellular carcinoma.

In the pre-DAA era, studies showed a reduction of HCC occurrence in patients with HCV who attained SVR. In a 2012 study by Adriaan J. van der Meer, MD, and colleagues, the 10-year cumulative occurrence rate of HCC was just 5.1% in patients who met SVR, in contrast to 21.8% in those who failed interferon-based therapies. A pooled analysis by Rebecca L. Morgan, MPH, and colleagues, in 2013 showed a significant reduction in HCC post-SVR: 1.5% of SVR patients developed HCC vs. 6.2% of non-SVR. Yet, at both the International Liver Congress in 2016 and subsequently, studies have led us, rather unexpectedly, to question whether DAA therapy may affect a patient adversely with regard to the development of HCC both in patients with a history of HCC and in a de novo fashion.

ILC 2016 Data

In a Late Breaking presentation in Barcelona, we saw data on 344 patients with HCV-related Child-Pugh A/B cirrhosis, without active HCC. They were treated with a variety of DAAs, with or without ribavirin, and occurrence of HCC was monitored through 6 months.

At the end of the follow-up period, 7.6% of all patients were diagnosed with HCC with 29% (17/59) of those with previous treated HCC showing recurrence. In contrast, only 3.2% (9/285) of those without such a history presented with de novo HCC.

In a similar vein, a study by María Reig, MD, and her Barcelona colleagues looked at 58 patients with a history of HCC followed by treatment with DAAs. They showed that 16 patients (27.6%) had radiologic recurrence within a median 5.7 months of follow-up. In a commentary on Reig’s study, Ju Dong Yang, MD, and colleagues showed that patients on the waiting list for liver transplant for HCV-associated HCC who received pre-transplant DAA therapy trended toward a higher HCC recurrence (27.8%) vs. their untreated counterparts (9.5%). The authors of this study did mention that three of the five patients who recurred in the treated group had not achieved SVR.

In decompensated cirrhotics, Michelle Cheung, MD, MPH, FAAP, showed no signal for increased rates of HCC after DAA-induced SVR. The researchers followed more than 406 patients up to 15 months and saw a 4% occurrence of HCC in the first 6 months, whether treated or untreated. In those who achieved SVR24, there was a 5.4% rate of HCC as compared to 4.2% in the untreated arm. In those that failed DAA therapy, the rate of HCC was 11.2%.

PAGE BREAK

Other studies have provided reassurance that an increased risk of HCC recurrence does not exist after successful DAA therapy. An important ANRS publication from France evaluated three separate patient cohorts derived from large multicenter studies of cirrhotic patients, and found no evidence of a significant increase in HCC incidence in SVR patients relative to untreated comparator populations. Moreover, a recent study from the Italian Liver Cancer Group suggested a similar reduction in HCC recurrence after successful treatment with either interferon-based or DAA therapies.

Ira M. Jacobson

So while it has been theorized that a loss of intrahepatic immune surveillance could be a mechanism for HCC recurrence after DAAs, the data is insufficient to change our current treatment recommendations, which is to treat everyone.

Yet if we allow for even the possibility of a trend toward recurrence, with a putative causative mechanism underlying this possibility, the question must be asked: could there be an increased risk of de novo HCC in the immediate aftermath of SVR? After all, a certain percentage of cirrhotics already harbor tumor cells that are still clinically or radiologically undetectable.

Liver Meeting Data

At The Liver Meeting, we saw one study where incident HCC initially appeared to be more common after sofosbuvir-based DAA therapy, but after adjustment for baseline patient features the trend was negated. In another study from Italy, researchers followed more than 3,000 patients with F3 and F4 cirrhosis treated with DAAs. In a mean follow-up of 300 days, 41 participants developed HCC for an incidence of 1.64% persons per year, which is not excessive. In this study, SVR12 was associated with a 0.20 hazard ratio.

The most provocative discussion arising from this Italian study presented by Alfredo Alberti, MD, came from their report of an increased appearance of HCC with more than three nodules: 33.3% in those who achieved SVR; 53.8% in those who did not achieve SVR; and 28.6% in those still pending SVR. So we question now if DAAs are impacting the etiology of the HCC that is occurring de novo after treatment.

With all of these studies in mind, many are questioning why HCC arises after SVR and if we can predict its appearance. A study presented by James Crismale, MD, at the Liver Meeting showed varied characteristics of patients with post-SVR HCC: 12% had pre-treatment steatosis, 29% did not have cirrhosis and there was an association with non-white patients and albumin less than 3.5 g/dL. With these findings, the authors called for investigation into biomarkers of HCC risk after SVR.

Using genome-wide association study in a Japanese cohort developing HCC more than 1 year after SVR, another set of researchers showed a nearly two-fold risk of HCC with the TLL1 SNP rs17047200. They concluded that TLL1 may contribute to HCC development via hepatic fibrogenesis. Due to the increased risk associated with this, they suggest genetic testing for the TLL1 SNP could help implement personalized surveillance of HCC post-SVR. This is an area that calls for extensive additional research.

PAGE BREAK

Looking Ahead

Though the data is limited to these studies as we are just now seeing long-term implications of DAAs, the frequency of HCC recurrence after DAA therapy is still controversial. We require larger studies but the existing evidence does not support the withholding of antiviral therapy from patients with HCV even with a history of HCC.

With regard to de novo HCC post-SVR, there remains incontrovertible evidence for a major reduction in de novo HCC risk after SVR. There is no convincing evidence for a transient “spike” in de novo HCC post-SVR with DAAs, but the question of an alteration in the biology of de novo HCC after SVR requires further study.

Most experts agree that it remains critical to screen for HCC after SVR in cirrhotic patients even if cirrhosis appears to regress. For patients with a history of HCC, clinicians must exercise individual judgement with regard to an increased frequency of surveillance beyond the standard of semiannual imaging for a period of time after antiviral therapy in patients considered to be at particular risk of recurrence.

Ira M. Jacobson, MD

HCV Next

Co-Chief Medical Editor