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


Search Strategy and Study Selection

With predefined search criteria including terms such as DAAs treatment, SVR, HCV, recurrence, relapse and reinfection (more details available in online Supporting Information), a search for suitable publications between 1 January 2011 and 31 October 2019 was performed using PubMed, Web of Science and the Cochrane Library by two independent authors (PH and YW) and updated in November 2020. We retrieved articles for studies reporting on HCV recurrence during long-term follow-up after DAAs-induced SVR. In addition, the reference lists of articles identified in the primary search were thoroughly screened to expand the search for other potentially relevant publications. Presentations at major international viral hepatitis conferences were also included in the search, including the International Liver Congress (European Association for the Study of the Liver), the Liver Meeting (American Association for the Study of Liver Diseases), the annual Conference on Retroviruses and Opportunistic Infections (CROI), and the International Symposium on Hepatitis Care in Substance Users.

All publications which met the following criteria were included in our analysis:

  • Study: Article types including original articles, correspondence, communication reports, conference abstracts and presentations (oral or posters) were eligible.

  • Population: Participants must have been adults (≥18 years old) chronically infected with HCV and a sample size of ≥10.

  • Treatment regimens and follow-up: Only studies reporting successful SVR from all-oral DAAs-based regimens with or without ribavirin (RBV) were included. Moreover, only studies with greater than 6 months (24 weeks) of post-SVR follow-up were included.

  • Outcome Measures: Reported overall HCV recurrence rates during the follow-up period were obtained.

The following publications were excluded from this analysis:

  1. Animal studies.

  2. Review articles and meta-analyses.

  3. Non-English studies.

  4. Recurrence after spontaneous (non-treatment-induced) viral clearance.

  5. Failure to specify SVR time period following cessation of DAAs therapy.

  6. Inestimable person-years of follow-up (PYFU).

  7. Special population studies involving patients undergoing liver or kidney transplantation.

Data Extraction and Quality Assessment

All eligible studies were subsequently divided into three population groups according to HCV reinfection risk level (low or high) or HIV/HCV coinfection as follows:

  1. Low-risk population: studies of HCV-mono-infected patients with no recognized risk factors for reinfection.

  2. High-risk population: studies of HCV-mono-infected patients with at least one identified risk factor for reinfection.

  3. HIV/HCV coinfection population.

Risk factors for reinfection were defined as current or former PWID, incarceration or MSM.

In terms of the HCV recurrence category, we distinguished late relapse from reinfection by analysing studies that performed phylogenetic analysis of HCV strains at pretreatment and at the time of HCV reappearance. Late relapse versus reinfection was characterized as by Simmons et al,[11] where identification of HCV RNA of the initial lineage indicated relapse and detection of a different lineage suggested reinfection. In genotyping studies where no information on classification was provided, the same definitions outlined in the present study have been applied. In some studies, categorization was done without confirmatory genotyping. In these studies, we have considered the possibility of reinfection and carefully evaluated the patient's recent potential exposure to HCV infection through high-risk behaviours. Overall, this classification was confirmed according to the protocol in the original study.

Two reviewers independently screened all publications generated by the search and relevant references to identify studies that fulfilled the inclusion criteria. Using standardized forms, the following details were extracted from all selected studies: study type and design, number, country, patient characteristics, number of patients achieving SVR, study follow-up duration, number of patients with HCV recurrence (late viral relapse and reinfection), the method of confirming late viral relapse or reinfection, and total PYFU post-SVR.

Person-years of follow-up were determined from the time SVR was achieved; in those studies where follow-up originated at a different time, PYFU were adjusted accordingly. If total PYFU was not explicitly stated, it was estimated based on the follow-up time and the time of recurrence, loss to follow-up post-SVR, or death. As follow-up for some studies began at the end of treatment (EOT), we pushed back the corresponding time to SVR12 assessment and then estimated person-years. In summary, all data were confirmed according to description in the original article. In the case of duplications, the publication with the most complete information available and longest follow-up period was included in this study.

The modified Newcastle–Ottawa Scale (NOS), which is commonly used to assess the quality of selection, comparability, exposure and outcome of study participants, was adapted to evaluate the quality of included observational studies (details in Supporting Information). A study could be awarded a maximum of eight stars. Selections with a NOS rating of ≥6 were considered high quality.[11] Discrepancies generated from NOS assessment by the two independent researchers were resolved by consensus.

Data Consolidation and Analysis

The incidence rate per 1000 PYFU was calculated by dividing the number of recurrences by the total PYFU and is presented with the corresponding 95% confidence interval (95% CI). In the case of zero events, we estimated the incidence rate by using Freeman–Tukey double arcsine transformation. Additionally, a correction factor of 0.5 was added to case events in studies with non-recurrence.[25]

Heterogeneity between the studies was analysed using I2, where an I2 of 0%-25% represents little or no heterogeneity; 25%-49% represents moderate heterogeneity; 50%-74% indicates substantial heterogeneity; and ≥75% indicates considerable heterogeneity.[11,26] When possible, meta-regression, subgroup analysis and sensitivity analysis were used to understand potential sources of heterogeneity. Furthermore, publication bias was examined by using funnel plots, and Egger's and Begg's tests. Leveraging integrated data from previous research,[11] we conducted a meta-regression analysis to compare the HCV recurrence risk after achieving SVR between DAAs therapy and IFN-based therapy.

The data were collected and integrated in Excel 2016 (Microsoft Office). All statistical analyses were performed using R version 3.5.2 (The R Foundation for Statistical Computing). All statistical tests were two-sided and a P value < .05 was set to denote statistical significance.