The Risk of Hepatitis C Virus Recurrence in Hepatitis C Virus-infected Patients Treated With Direct-acting Antivirals After Achieving a Sustained Virological Response

A Comprehensive Analysis

Peng Huang; Yan Wang; Ming Yue; Zhijun Ge; Xueshan Xia; Andre J. Jeyarajan; Jacinta A. Holmes; Rongbin Yu; Chuanwu Zhu; Sheng Yang; Wenyu Lin; Raymond T. Chung


Liver International. 2021;41(10):2341-2357. 

In This Article

Abstract and Introduction


Background & Aims: The risk for hepatitis C virus (HCV) recurrence persists after HCV eradication with direct-acting antivirals (DAAs), particularly in patients with ongoing high-risk behaviours. Our aim was to assess the risk of HCV recurrence (late relapse and/or reinfection) post-sustained virological response (SVR).

Methods: We searched the literature for studies reporting HCV recurrence rates post-SVR in PubMed, Web of Science and the Cochrane Library. Identified publications were divided into groups based on patient risk for HCV reinfection: low-risk HCV mono-infection, high-risk HCV mono-infection and a human immunodeficiency virus (HIV)/HCV coinfection. The HCV recurrence rate for each study was calculated by using events divided by the person-years of follow-up (PYFU). HCV recurrence was defined as confirmed, detectable HCV RNA post-SVR.

Results: In the 16 studies of low-risk patients, the pooled recurrence rate was 0.89/1000 PYFU (95% confidence interval [CI], 0.16–2.03). For the 19 studies of high-risk patients, the pooled recurrence rate was 29.37/1000 PYFU (95% CI, 15.54–46.91). For the eight studies of HIV/HCV-coinfected patients, the pooled recurrence rate was 23.25/1000 PYFU (95% CI, 4.24–53.39). The higher pooled estimates of recurrence in the high-risk and HIV/HCV-coinfected populations were predominantly driven by an increase in reinfection rather than late relapse.

Conclusions: The HCV recurrence risk after achieving SVR with all-oral DAAs therapy is low, and the risk of HCV recurrence in high-risk and HIV/HCV-coinfected populations was driven by an increase in reinfection rather than late relapse.


Hepatitis C virus (HCV) remains a global health issue. According to the World Health Organization (WHO), it has been estimated that more than 71 million individuals are chronically infected with HCV.[1] Chronic HCV infection can gradually progress to advanced liver fibrosis and cirrhosis, and lead to complications such as end-stage liver disease and hepatocellular carcinoma (HCC).[2]

Highly effective, well-tolerated interferon-free (IFN-free) direct-acting antivirals (DAAs) have revolutionized the treatment of HCV, providing a 'cure' of infection for more than 95% of individuals.[3,4] Owing to the success of these highly effective regimens, the WHO has set the goal of eliminating viral hepatitis, including HCV infection, as a public health concern by 2030, reducing new diagnoses of viral hepatitis by 90% and mortality by 65%.[5] The primary goal of hepatitis C treatment is to eradicate HCV and obtain a sustained virological response (SVR), defined as undetectable HCV RNA levels 12 weeks following the completion of therapy.[6] The attainment of SVR results in clinical benefits for patients, including improvement in hepatic outcomes ranging from normalization of liver function, fibrosis regression and reduction in the risk of liver-related morbidity and mortality, as well as extrahepatic manifestations, such as improvement in the risk of diabetes, cryoglobulinaemia, health-related quality of life and all-cause mortality.[7–10]

However, a remaining concern is the risk of HCV recurrence, defined as confirmed detectable HCV RNA following documented SVR with antiviral therapy. Recurrent viraemia can be classified as either late relapse or reinfection.[11] Although rare, HCV recurrence is more common in patients with ongoing high-risk behaviours, such as persons who inject drugs (PWID), incarceration, men who have sex with men (MSM), and in individuals coinfected with human immunodeficiency virus (HIV) who are vulnerable due to immune system dysfunction.[12–16]

Although it has been reported that most patients with recurrent viraemia after discontinuation of HCV treatment experienced recurrence early after stopping treatment (post-treatment Week 4 or 12), routine monitoring of HCV RNA levels already occurs between the end of treatment and the time SVR is achieved.[17] Investigations involving long-term (greater than 6 months) follow-up of patients with interferon (IFN)-induced SVR have found that approximately 80%-100% of patients maintained SVR.[11] However, the long-term durability of SVR in the setting of DAAs treatment is still unclear. Thus, we sought to investigate the prolonged outcomes of DAAs-induced SVR. There have been several studies evaluating the durability of treatment-induced SVR in patients with chronic HCV, especially in individuals with ongoing high-risk behaviours.[13,18–23] Furthermore, there have been two systematic reviews evaluating the rate of HCV recurrence; one evaluated the risk of late relapse or reinfection after achieving SVR in the IFN era,[11] and the other assessed the HCV reinfection rate after successful antiviral treatment among PWID.[24] However, to our knowledge, there has been no comprehensive analysis that summarizes the HCV recurrence risk post-SVR following DAAs-based therapy. Therefore, we conducted this analysis to evaluate the rate of HCV recurrence among patients of various risk status and address the long-term risk of HCV recurrence. This study provides deeper insight into the extended outcomes of DAAs treatment and may also assist in establishing policies and recommendations to meet WHO elimination targets by 2030.