In the Journals

Liver cancer incidence after HCV therapy linked to risk factors, not treatment

Direct-acting antiviral treatment for hepatitis C did not correlate with an increased risk for hepatocellular carcinoma in a large cohort study of both treated and untreated patients with or without cirrhosis. Those with incident HCC after DAA treatment had higher risk factors at baseline.

Raymond T. Chung, PhD
Raymond T. Chung

“There was no increased risk for HCC as a result of having received DAA therapy whatsoever,” Raymond T. Chung, MD, director of Hepatology and Liver Center at Massachusetts General Hospital, told Healio Gastroenterology and Liver Disease. “The risk was related to their preexisting likelihood of developing HCC. The fact that HCC developed post-DAA, we think, is more likely to be an accident of timing than the idea that it's related to receipt of DAA — these persons were at risk for HCC whether they received DAAs or not.”

“The initial reports put physicians into a state of concern about treating such patients,” Chung continued, “but ours and several other studies all align in that the DAAs themselves do not appear to be independently associated with an increased risk for HCC.”

Chung and colleagues conducted a retrospective study using patient data from the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database to assess the development of incident HCC 3 months or more from baseline.

The 17,836 patients with HCV included in the study had previously received treatment with pegylated interferon and ribavirin, DAAs, or were untreated.

Patients treated with DAAs received one of the following with ribavirin: Harvoni (sofosbuvir/ledipasvir, Gilead Sciences); combination Olysio (simeprevir, Gilead Sciences) and Sovaldi (sofosbuvir, Gilead Sciences); Viekira Pak (ombitasvir/paritaprevir/ritonavir; dasabuvir, AbbVie); or combination sofosbuvir and daclatasvir.

Most patients were men and had clinically similar median HCV RNA levels and BMI. Compared with patients treated with interferon, those treated with DAAs were significantly older (62 vs. 54 years; P < .01), more often had cirrhosis (19.9% vs. 13.1%; P < .01) and diabetes (30.9% vs. 17.6%; P < .01), had higher median alpha-fetoprotein levels (4.3 vs. 3.2 IU/mL; P < .01).

During a mean follow-up of 2,719.2 days for IFN-treated patients and 396.4 days for DAA-treated patients, the researchers observed 196 and 50 incident cases of HCC, respectively.

HCC incidence

Chung and colleagues performed their primary analysis in patients with cirrhosis and found no significant difference in HCC incidence between those who received DAA or IFN therapy. However, untreated patients with cirrhosis had a significantly higher rate of HCC compared with treated patients (45.31 per 1,000 person-years; P = .03).

Similarly, treated patients with cirrhosis who did not achieve SVR had higher rates of HCC, though this did not differ between treatment with DAAs or IFN. Treated patients with cirrhosis who achieved SVR had a significantly lower risk for HCC (P = .0004).

Among patients with FIB-4 data within 12 months of baseline, DAA treatment correlated with a significantly lower HCC rate compared with IFN among patients with cirrhosis (17.9 vs. 31.99 per 1,000 person-years; P < .01), though not between treatment groups in patients who achieved SVR.

“It's always important to stage our patients with hepatitis C as they embark on a course of antiviral therapy because of the implications for follow-up care,” Chung said. “Patients with advanced fibrosis require continued screening for HCC, whether they are treated with DAAs or not.”

“Clinicians should not be deterred in treating those patients with advanced fibrosis,” Chung continued. “Rather, this is a group that most needs therapy to interrupt their natural history and ultimately reduce their risk for complications, including HCC.”

During an analysis of all patients who achieved SVR with DAA therapy, the researchers found a higher rate of HCC compared with IFN-treated patients (7.41 vs. 3.48 per 1,000 person-years; P < .01). However, HCC rates between treatment groups did not differ among those who did not achieve SVR.

Another subgroup analysis of HCC rates in patients treated with IFN-free DAA therapy showed that patients treated with simeprevir or sofosbuvir had higher baseline rates of cirrhosis compared with those treated with IFN (39.6% vs. 13.1%; P < .01) or sofosbuvir/ledipasvir (39.6% vs. 18.9%; P < .01).

Final analysis

Among patients with cirrhosis, DAA treatment did not correlate with a higher risk for HCC compared with IFN treatment (HR = 1.07; 95% CI, 0.55-2.08).

The risk for incident HCC was higher, however, among patients with known HCC risk factors such as older age (HR =1.76 per 10-year increase; 95% CI, 1.26-2.46) and AFP levels higher than 20 at baseline (HR = 4.1; 95% CI, 2.75-6.1). Statin use correlated with a lower risk for HCC (HR = 0.5; 95% CI, 0.31-0.8), whereas PPI use correlated with a higher risk (HR = 1.65; 95% CI, 1.07-2.55).

There was no difference in HCC-free survival between the two treatment groups.

While successful SVR did not correlate with a significantly lower HCC rate in the primary analysis, the researchers found that SVR was statistically significant after a multivariable analysis that limited the baseline FIB-4 to within a 12-month period prior to baseline (HR = 0.6; 95% CI, 0.38-0.93).

“We don't want to dissuade physicians from treating people with advanced fibrosis and cirrhosis due to hepatitis C from getting treatment they really need,” Chung concluded. – by Talitha Bennett

Disclosure: Chung reports he was supported by NIH DK078772 and the MGH Research Scholars Program. Please see the full study for the other researchers’ relevant financial disclosures.

Direct-acting antiviral treatment for hepatitis C did not correlate with an increased risk for hepatocellular carcinoma in a large cohort study of both treated and untreated patients with or without cirrhosis. Those with incident HCC after DAA treatment had higher risk factors at baseline.

Raymond T. Chung, PhD
Raymond T. Chung

“There was no increased risk for HCC as a result of having received DAA therapy whatsoever,” Raymond T. Chung, MD, director of Hepatology and Liver Center at Massachusetts General Hospital, told Healio Gastroenterology and Liver Disease. “The risk was related to their preexisting likelihood of developing HCC. The fact that HCC developed post-DAA, we think, is more likely to be an accident of timing than the idea that it's related to receipt of DAA — these persons were at risk for HCC whether they received DAAs or not.”

“The initial reports put physicians into a state of concern about treating such patients,” Chung continued, “but ours and several other studies all align in that the DAAs themselves do not appear to be independently associated with an increased risk for HCC.”

Chung and colleagues conducted a retrospective study using patient data from the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database to assess the development of incident HCC 3 months or more from baseline.

The 17,836 patients with HCV included in the study had previously received treatment with pegylated interferon and ribavirin, DAAs, or were untreated.

Patients treated with DAAs received one of the following with ribavirin: Harvoni (sofosbuvir/ledipasvir, Gilead Sciences); combination Olysio (simeprevir, Gilead Sciences) and Sovaldi (sofosbuvir, Gilead Sciences); Viekira Pak (ombitasvir/paritaprevir/ritonavir; dasabuvir, AbbVie); or combination sofosbuvir and daclatasvir.

Most patients were men and had clinically similar median HCV RNA levels and BMI. Compared with patients treated with interferon, those treated with DAAs were significantly older (62 vs. 54 years; P < .01), more often had cirrhosis (19.9% vs. 13.1%; P < .01) and diabetes (30.9% vs. 17.6%; P < .01), had higher median alpha-fetoprotein levels (4.3 vs. 3.2 IU/mL; P < .01).

During a mean follow-up of 2,719.2 days for IFN-treated patients and 396.4 days for DAA-treated patients, the researchers observed 196 and 50 incident cases of HCC, respectively.

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HCC incidence

Chung and colleagues performed their primary analysis in patients with cirrhosis and found no significant difference in HCC incidence between those who received DAA or IFN therapy. However, untreated patients with cirrhosis had a significantly higher rate of HCC compared with treated patients (45.31 per 1,000 person-years; P = .03).

Similarly, treated patients with cirrhosis who did not achieve SVR had higher rates of HCC, though this did not differ between treatment with DAAs or IFN. Treated patients with cirrhosis who achieved SVR had a significantly lower risk for HCC (P = .0004).

Among patients with FIB-4 data within 12 months of baseline, DAA treatment correlated with a significantly lower HCC rate compared with IFN among patients with cirrhosis (17.9 vs. 31.99 per 1,000 person-years; P < .01), though not between treatment groups in patients who achieved SVR.

“It's always important to stage our patients with hepatitis C as they embark on a course of antiviral therapy because of the implications for follow-up care,” Chung said. “Patients with advanced fibrosis require continued screening for HCC, whether they are treated with DAAs or not.”

“Clinicians should not be deterred in treating those patients with advanced fibrosis,” Chung continued. “Rather, this is a group that most needs therapy to interrupt their natural history and ultimately reduce their risk for complications, including HCC.”

During an analysis of all patients who achieved SVR with DAA therapy, the researchers found a higher rate of HCC compared with IFN-treated patients (7.41 vs. 3.48 per 1,000 person-years; P < .01). However, HCC rates between treatment groups did not differ among those who did not achieve SVR.

Another subgroup analysis of HCC rates in patients treated with IFN-free DAA therapy showed that patients treated with simeprevir or sofosbuvir had higher baseline rates of cirrhosis compared with those treated with IFN (39.6% vs. 13.1%; P < .01) or sofosbuvir/ledipasvir (39.6% vs. 18.9%; P < .01).

PAGE BREAK

Final analysis

Among patients with cirrhosis, DAA treatment did not correlate with a higher risk for HCC compared with IFN treatment (HR = 1.07; 95% CI, 0.55-2.08).

The risk for incident HCC was higher, however, among patients with known HCC risk factors such as older age (HR =1.76 per 10-year increase; 95% CI, 1.26-2.46) and AFP levels higher than 20 at baseline (HR = 4.1; 95% CI, 2.75-6.1). Statin use correlated with a lower risk for HCC (HR = 0.5; 95% CI, 0.31-0.8), whereas PPI use correlated with a higher risk (HR = 1.65; 95% CI, 1.07-2.55).

There was no difference in HCC-free survival between the two treatment groups.

While successful SVR did not correlate with a significantly lower HCC rate in the primary analysis, the researchers found that SVR was statistically significant after a multivariable analysis that limited the baseline FIB-4 to within a 12-month period prior to baseline (HR = 0.6; 95% CI, 0.38-0.93).

“We don't want to dissuade physicians from treating people with advanced fibrosis and cirrhosis due to hepatitis C from getting treatment they really need,” Chung concluded. – by Talitha Bennett

Disclosure: Chung reports he was supported by NIH DK078772 and the MGH Research Scholars Program. Please see the full study for the other researchers’ relevant financial disclosures.