Study Shows DAAs Are Not Associated With Increased HCC Recurrence Risk


Direct acting antivirals are a novel and completely oral hepatitis C therapy that is associated with a high response rate in hepatocellular carcinoma (HCC).

Amit G. Singal, MD, MS

Amit G. Singal, MD, MS

Amit G. Singal, MD, MS

Direct acting antivirals (DAA) are a novel and completely oral hepatitis C therapy that is associated with a high response rate. DAAs are used in most patients being treated for hepatitis C, including those with decompensated cirrhosis.

This type of treatment has now completely replaced interferon-based therapy for patients with hepatitis C, a therapy which was also associated with a decrease in hepatocellular carcinoma (HCC) incidence in 40% to 50% of patients.

Initially, it was thought that DAAs would also decrease HCC recurrence, but a multicenter, single-arm, retrospective study out of Spain demonstrated an increase in the early recurrence of HCC following treatment with DAAs. Among 58 patients with a history of HCC and a complete response early recurrence was observed in 16 patients (27.6%) when treated with DAA.

“There have been several subsequent studies that show conflicting results in terms of this question,” said Amit G. Singal, MD. “Some studies show a high recurrence rate, and some show a relatively low recurrence rate.”

In his presentation during the 2017 International Liver Cancer Association Annual Conference, Singal addressed this fear that healthcare providers now have of DAAs.1

Singal noted that many of these conflicting studies have had limitations, such as small sample size, short duration of follow-up, and lack of comparator arm. For example, in a study by Dr Tatsuya Minami et al, of 27 patients, the recurrence rate at 2 years was 29.8%,2 while in a study by Pol, et al, there was only a 9.0% recurrence rate with 189 patients evaluated.3

“As you can imagine, this created fear that there may be unintended effects from treatment with the DAAs and selecting groups of patients,” said Singal.

In a study evaluating the association between DAA therapy and HCC recurrence among patients with HCC who achieved a complete response (CR), Singal aimed to clear up conflicting data surrounding DAAs.

The multicenter, cohort study in the United States included adult patients with hepatitis C-related HCC with CR per modified RECIST criteria after resection, local ablative therapies, transarterial chemoembolization, stereotactic body radiation therapy, or transarterial radioembolization from January 2013 to December 2016. The primary endpoints were proportion of patients with HCC recurrence and time to recurrence.

In the treatment arm, patients eligible were treated with DAA for any period of time (n = 207). The control arm included only patients with HCC CR and no DAA exposure (n = 127). The median age for the DAA-treated group was 63 years (72%) versus 61 years (81%) for the DAA-naïve patients. Of the DAA-treated patients, 180 (87%) were early stage via Milan criteria, and 103 (83%) were early stage in the DAA-naïve group.

Median follow-up was 24.1 (17.0-32.4) months for the DAA-treated populations, and 15.9 (9.2-23.0) months for the DAA-naïve patients (P <.001).

An interim analysis at a median 20.7-month follow-up showed that HCC recurrence was not higher in patients treated with DAAs; recurrence overall was observed in 47.6% of patients. Recurrence was observed in 95 patients treated with DAAs (45.9%) versus 64 DAA-naïve patients (P = .42). Also, early recurrence was not higher in patients treated with DAA, with 15 patients with DAA showing early recurrence (7.3%) versus 14 (11.0%) in DAA-naïve patients (P = 0.23).

“We found DAAs did not have an association with increased recurrence, and the recurrence rates between the 2 groups were similar,” said Singal. “If anything, the time to recurrence was longer in the DAA-treated group than the untreated group.”

Therapy with DAAs was associated with longer time to HCC recurrence, with the median time-to-recurrence in the DAA-treated patients at 13.4 months versus 8.0 months in the DAA-naïve patients (P <.001).

These results summarize the safety of DAAs in regard to HCC recurrence. Additionally, patients who are not treated with DAAs may have lower rates of treatment eligibility and response rates, he noted.

“Further studies with longer follow-up and careful evaluation for HCC recurrence are still needed. However, the hope is that this will offer some reassurance to providers that DAAs are likely safe in these patients who had HCC and had a complete response and that they can be used to cure the hepatitis C in these patients.”


  1. 1. Singal AG, Hoteit M, John BV, et al. Direct acting antiviral therapy is associated with shorter time to HCC recurrence but not increased risk of recurrence. In: Proceedings from the 2017 International Liver Cancer Association Annual Conference; September 15-17, 2017; Seoul, South Korea. Abstract 0-021.
  2. 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(6):1272-1273. doi: 10.1016/j.jhep.2016.07.043.
  3. The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). 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(4):734-40. doi: 10.1016/j.jhep.2016.05.045.

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