Published online Oct 28, 2019. doi: 10.3748/wjg.v25.i40.6094
Peer-review started: June 17, 2019
First decision: July 21, 2019
Revised: August 9, 2019
Accepted: September 9, 2019
Article in press: September 9, 2019
Published online: October 28, 2019
Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of a sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established.
The main topic of this study was to establish the effectiveness of new generations of DAAs to induce SVR and to prevent HCC development or mortality in HCV-infected patients. These patients were characterized by an elevated risk for HCC because of their advanced or complicated liver disease. The strength of this study was the use of a multi-state Cox-Markov model. This model permitted us to explore more deeply the relationships of baseline variables with events in each different disease state. This last approach is not possible with a classical survival Cox model.
The aim of this study was to examine HCC occurrence or death from any cause in a retrospective-prospective study of patients treated with DAAs and to identify potential predictors of SVR achievement and HCC development.
The patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted using 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders. Survival analysis was conducted using a classical Cox model and a more advanced Cox-Markov multi-state model that considered SVR as a time-dependent variable that can influence the probability of the outcome.
The incidence rates of HCC in patients with and without SVR were 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, independent predictors of SVR achievement were the absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).
Treatment with DAAs is very effective in inducing SVR and protecting against HCC or death. A residual risk for HCC persists in patients with advanced liver disease or disease complicated by extra-hepatic manifestations, such as mixed cryoglobulinemia and renal failure.
New generations of DAAs should be recommended to treat all patients with HCV infection independently of the status of their liver disease or the presence of extra-hepatic manifestations. Further studies are needed to define a better strategy to treat HCV-infected patients with more advanced or complicated liver disease.