Spotlight on direct-acting antivirals

Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection are associated with higher survival rates after liver transplantation and lower all-cause mortality and hepatocellular carcinoma (HCC) incidence, but not with decompensated cirrhosis or HCC recurrence, according to three recent studies.

In the first study, published online on Feb. 4 by Liver Transplantation, researchers used the Scientific Registry of Transplant Recipients to assess long-term outcomes of 52,526 patients who received liver transplants from Jan. 1, 2008, to June 30, 2018, in the U.S. They compared graft survival among HCV-positive and HCV-negative transplant recipients with HCV-positive or -negative donors (three groups: D-/R+, D+/R+, and D-/R-). They further divided the groups into pre-DAA and DAA eras, with November 2013 as the cutoff, based on FDA approval of simeprevir and sofosbuvir.

There were 31,193 D-/R-, 18,746 D-/R+, and 2,587 D+/R+ transplants during the study period. The number of D-/R+ transplants decreased from 2,010 in 2008 to 1,334 in 2017, a decline that was particularly evident since 2015. While all transplant recipients saw improvements in graft survival, HCV-positive recipients had the most dramatic improvements. For D-/R+ patients in the DAA era versus pre-DAA era, one-year survival was 92.4% versus 88.7%, and three-year survival was 83.7% versus 77.7%, respectively. In contrast, among D-/R- patients, one-year survival was 92.7% versus 91.0%, and three-year survival was 85.7% versus 84.0% (for the DAA era vs. pre-DAA era, respectively). Limitations noted by the authors include the study's retrospective design and the inability to conduct a more detailed outcome analysis based on HCV treatment or sustained virologic response.

In the second study, researchers prospectively compared the incidence of all-cause mortality, HCC, and decompensated cirrhosis between untreated patients and those treated with DAAs in the French ANRS CO22 HEPATHER cohort. Results of the study, which was funded in part by industry, were published online on Feb. 11 by the Lancet.

During a median follow-up of 33.4 months, treatment with DAAs was initiated in 7,344 patients, whereas 2,551 patients remained untreated at the final follow-up visit. Overall, 218 patients died (129 treated, 89 untreated), 258 reported HCC (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). After adjustment for potential confounding factors, exposure to DAAs was associated with decreases in all-cause mortality (adjusted hazard ratio, 0.48; 95% CI, 0.33 to 0.70) and HCC (hazard ratio, 0.66; 95% CI, 0.46 to 0.93), and was not associated with decompensated cirrhosis (hazard ratio, 1.14; 95% CI, 0.57 to 2.27).

Limitations of the study include its observational nature and short duration of follow-up, the authors noted. Although correlation does not equal causation, they presented plausible mechanisms for the relationship between DAAs and mortality and incidence of HCC. “Direct-acting antivirals induce a sustained virological response, reducing liver damage and inflammation,” they wrote. “This effect causes liver regeneration, decreasing risk for progression to liver-related complications or hepatocellular carcinoma.”

The third and final study, which was partly industry funded and was published online on Jan. 17 by Gastroenterology, looked at a population with previous HCC. Researchers retrospectively compared HCC recurrence patterns in 793 patients whose HCV infection was either untreated or treated with DAAs. Patients had had a complete response to HCC treatment from January 2013 through December 2017 at 31 health systems throughout the U.S. and Canada.

Overall, 304 (38.3%) patients received DAA therapy, and 489 (61.7%) were untreated. A total of 128 (42.1%) DAA-treated patients had HCC recurrence, 52 (40.6%) of whom had early recurrence (i.e., within 365 days after complete response). Of the untreated patients, 288 (58.9%) had HCC recurrence, and 227 (78.8%) had early recurrence. After various adjustments, DAA therapy was not associated with HCC recurrence (hazard ratio, 0.90; 95% CI, 0.70 to 1.16) or early HCC recurrence (hazard ratio, 0.96; 95% CI, 0.70 to 1.34).

The study authors noted limitations, such as the potential for missed cases, misclassification of early versus late recurrences, and residual confounding. “Overall, our results suggest use of DAA therapies is safe and potentially beneficial in HCV-infected patients with a history of HCC,” they concluded.