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. Author manuscript; available in PMC: 2022 Oct 1.
Published in final edited form as: Liver Int. 2021 Jun 16;41(10):2341–2357. doi: 10.1111/liv.14976

The Risk of HCV Recurrence in HCV-infected Patients Treated with DAAs after Achieving a Sustained Virological Response: A Comprehensive Analysis

Peng Huang 1,2,*, Yan Wang 1,*, Ming Yue 3, Zhijun Ge 4, Xueshan Xia 5, Andre J Jeyarajan 2, Jacinta A Holmes 6, Rongbin Yu 1, Chuanwu Zhu 7, Sheng Yang 8,, Wenyu Lin 2,, Raymond T Chung 2,
PMCID: PMC8455436  NIHMSID: NIHMS1709869  PMID: 34051040

Abstract

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 behaviors. 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 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 8 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.

Keywords: Hepatitis C virus, direct-acting antivirals, sustained virological response, relapse, reinfection

INTRODUCTION

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 HCV1. 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 individuals3, 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 completion of therapy6. 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, cryoglobulinemia, health-related quality of life and all-cause mortality710.

However, a remaining concern is the risk of HCV recurrence, defined as confirmed detectable HCV RNA following documented SVR with antiviral therapy. Recurrent viremia can be classified as either late relapse or reinfection11. Although rare, HCV recurrence is more common in patients with ongoing high-risk behaviors, 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 dysfunction1216.

Although it has been reported that most patients with recurrent viremia 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 achieved17. Investigations involving long-term (greater than six months) follow-up of patients with interferon (IFN)-induced SVR have found that approximately 80%−100% of patients maintained SVR11. 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 behaviors13, 1823. 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 era11 and the other assessed the HCV reinfection rate after successful antiviral treatment among PWID24. 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.

METHODS

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 (P.H. and Y.W.) 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 ≥ 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 analyzing 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 al11, 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 behaviors. 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, ClinicalTrials.gov 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.

PYFU 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 was 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 8 stars. Selections with a NOS rating ≥6 were considered high quality11. 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 analyzed 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 heterogeneity11, 26. When possible, meta-regression, sub-group 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 research11, 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, Redmond, USA). All statistical analyses were performed using R version 3.5.2 (The R Foundation for Statistical Computing, Vienna, Austria). All statistical tests were two-sided and a P value < 0.05 was set to denote statistical significance.

RESULTS

The flow diagram detailing the database searches and included publications is illustrated in Figure 1. In summary, a total of 2,471 references were identified and screened for eligibility. Of these, results were available from 38 studies reporting on recurrence post-SVR. The study characteristics are shown in Table 1.

Figure 1. Literature screening flow diagram.

Figure 1.

Low-risk HCV mono-infected studies included those examining recurrence among patients with no recognized ongoing risk factors for reinfection (current or former PWID, incarceration, MSM, or active substance abuse). High-risk HCV mono-infected studies included those studying patients with at least one ongoing identified reinfection risk factor. HIV/HCV coinfected studies included all coinfected participants regardless of risk factors. The total number of studies in the three groups does not equal the total number of studies identified as five studies examined two populations.

Table 1.

Characteristics of Included Studies

Author Year Article type Location and study design(ClinicalTrials.gov number) Recruitment and exclusion criteria Start point Follow-up Frequency of HCV RNA testing NOS score
Carey et al (34) 2013 Conference Report NR; a observational study of clinical trials Enrolled patients who mono-infected HCV within the clinical trials SVR12 48weeks of EOT At post-treatment weeks 12, 24 and 48 5
Rutter et al (32) 2013 Original article Austria; a long-term follow-up of randomized, controlled trials (NCT00980330;NCT00882908; NCT00984620;NCT00869661;NCT01220947;NCT01331850) Enrollment from out-patient clinics with SVR SVR24 21(7–64) months of SVR At least once a year 6
Zeuzem et al (38) 2015 Conference Report Multi-country; a long-term follow-up of 6 phase 3 trials (NCT01704755;NCT01833533; NCT017 16585;NCT01715415;NCT01674725) Enrolled from the PEARL, SAPPHIRE and TURQUOISE-Ⅱ study with or without compensated cirrhosis SVR12 48weeks of EOT At post-treatment weeks 12, 24 and 48 5
Howe et al (24) 2015 Original article Multi-country; a long-term follow-up of phase 2 and phase 3 studies (NCT00423670;NCT00708500; NCT00705432;NCT00160251) Enrolled genotype-1 with compensated liver disease SVR24 3.4(0.5–4.1) years of SOT Every 3 months for 6 months, and then every 6 months 7
Lawitz et al (42) 2016 Conference Report Multi-country; a prospective cohort study (NCT01457755) Enrolled in a Gilead-sponsored study SVR12 71(0–156) weeks of EOT Every 6 months 6
Muir et al (41) 2016 Conference Report Multi-country; a prospective cohort study (NCT02292706) Enrolled patients who achieved SVR in a Gilead-sponsored study or clinical practice SVR12 85(8–187) weeks of EOT Every 6 months 6
Bourlière et al (39) 2017 Conference Report NR; a prospective cohort study Enrolled in the Gilead SVR Registry with no or minimal fibrosis SVR24 1.9(0–3.3) years of SVR Every 24 weeks for up to 144 weeks 6
Jacobson et al (43) 2018 Conference Report NR; a prospective cohort study Enrolled in the Gilead SVR Registry with F2 or F3 fibrosis SVR24 2.4(0–3.8) years of SVR Every 24 weeks through 144 weeks 6
Hayashi et al (37) 2018 Original article Japan; a long-term follow-up cohort study Enrollment from hospital clinic with genotype-1 infection; No HIV or HBV co-infection SVR24 21.5(4.8–30.3) months of SVR NR 6
Hayashi K et al (44) 2018 Original article Japan; a long-term follow-up cohort study Enrollment from hospital clinic with achieved SVR24; No HIV or HBV SVR24 6.0(1.0–13.6) years of SVR Every 6 or 12 months 6
Reddy et al (18) 2018 Original article Multi-country; a long-term follow-up of phase 2 or 3 observational study (NCT01492504) Enrolled patients for chronic HCV infection in phase 2 or 3 studies with type and frequency of hepatic disease progression SVR12 111(11–246) weeks of SVR At follow-up weeks 24, 48, 72, 96, 120 and 144 7
Zoulim et al (31) 2018 Original article Multi-country; a prospective cohort study (NCT01349465;NCT00980330;NCT00882908;NCT01289782;NCT01290679;NCT01281839) Enrolled patients who completed a previous Phase IIb or Phase III study SVR24 35.8(6.7–38.4) months of SVR Every 6 months up to 36 months 7
Mangia et al (40) 2018 Conference Report NR; a long-term observational cohort study Enrolled from the Gilead Cirrhosis Registry with compensated or decompensated cirrhosis who achieved SVR SVR12 71(<1–146) weeks of SVR Every 6 months 6
Kozbial et al (35) 2018 Original article Austria; a long-term follow-up cohort study (NCT02628717) Registered within the AURIC study with advanced liver disease; No HIV or HBV co-infection SVR12 65.6(13.0–155.3) weeks of EOT At post-treatment weeks 24, and 48, and then twice or once yearly 6
Flisiak et al (33) 2018 Original article Poland; a long-term follow-up cohort study Enrollment from hematologic clinics with genotype-1 or 4 in the AMBER study; No HBV or HCC SVR12 2years of EOT Single assessment 7
Manoj et al (36) 2018 Original article India; a prospective cohort study (NCT02563665) Enrollment from hospital clinic with CKD SVR12 72weeks of EOT At 24, 48 and 72 weeks after end of therapy 6
Dore et al (46) 2017 Conference abstract Multi-country; a long-term follow-up of phase 3, randomized trial (NCT02105688) Enrolled patients with genotype-1, 4, or 6 infection on OAT for no less than 3 months SVR12 2.29(0.25–2.35) years of SVR Every 6 months 6
Ingiliz et al (48) 2018 Conference abstract Germany; a multicenter prospective cohort study Enrolled patients with MSM or PWID from the German hepatitis C cohort SVR12 26(4–205) weeks of SVR NR 5
Cuadrado et al (15) 2018 Original article Spain; an open-label, single-arm, phase 4 clinical trial (NCT02768961) Enrolled patients from inmate population imprisoned SVR12 1.75years of SVR Every 6 months 7
Bouscaillou et al (45) 2018 Conference Report USA; a observational prospective cohort study Enrollment from PWID who were successfully treated for HCV SVR12 12(7.5–12) months of SVR Every 6 months 6
Schubert et al (50) 2018 Conference abstract Austria; an open-label, prospective cohort study Enrolled patients with OAT under direct observation of a pharmacist, physician or nurse at a pharmacy or at the ASW SVR12 13 months of SVR Every 3 months 6
Midgard et al (52) 2018 Conference Report Norway; a prospective cohort study Enrolled patients with recent (past 6 months) injecting drug use and an ETR to DAAs treatment SVR12 10 months of EOT Every 3 months 4
Bhandari et al (49) 2020 Original article North East England; a prospective cohort study Enrolled patients from seven prisons with chronic HCV infection SVR12 13(7–25)months of SVR NR 6
Rahman et al (47) 2019 Original article Bangladesh; a prospective observational study Enrolled patients who inject drug use in the previous two months or inject drug use and currently receive OAT; No HIV SVR12 6months of SVR Single assessment 6
Holeksa et al (51) 2019 Original article Canada; a retrospective cohort study Enrollment from VIDC PWID who were successfully treated for HCV SVR12 714(134–1841) days of SVR Every 6 months 6
Marco et al (53) 2019 Original article Spain; Multicenter, retrospective cohort study Enrolled patients treated in prison who had obtained SVR from all 11 Catalan prisons SVR 3.58years of SVR Every 12 months 6
Cunningham et al (54) 2020 Original article Multi-country; a long-term follow-up of multicenter, open-label phase 4 trials (NCT0233 6139; NCT02498015) Enrolled participants who achieved an ETR had recently injected drugs or currently receiving OAT; No HIV SVR12 108 weeks of EOT Every 3 months to 60 weeks and then every 6 months 7
Akiyama et al (55) 2020 Original article USA; a long-term follow-up of a 3-arm randomized, controlled trial (R01DA034086) Enrolled all of those who achieved SVR in the PREVAIL extension study and those lost to follow-up SVR12 20.5(SD=11.7) months of EOT Every 6 months to 24 months 7
Chan et al (56) 2020 Original article USA; a retrospective observational cohort study Enrolled patients in New York City jails SVR12 500(235–814) days of SVR Single assessment 6
Habchi et al (57) 2020 Original article USA; a retrospective observational study Enrolled patients on OAT at 1 of CODAC’s 8 community sites and attending at least 1 HCV visit SVR12 NR NR 6
Alimohammadi et al (14) 2018 Original article Canada; a retrospective cohort study Enrollment from hospital clinic including mostly of PWID SVR12 80(1–155) weeks of SVR Every 6 months 7
Rossi et al (22) 2018 Original article Canada; a retrospective cohort study Registered in the BC-HT cohort with SVR including PWID or at least moderate fibrosis SVR (10–52) 123(IQR84–357)days of SVR NR 6
Wyles et al (28) 2018 Brief report NR; a observational long-term follow-up prospective study Enrolled participants within 1 year of completion of treatment in clinical trials or in practice; No HBV, cirrhosis or CKD SVR12 112(66–203) weeks of SVR Every 6 months 7
Selfridge et al (29) 2019 Original article Canada; a observational retrospective study Enrolled participants who received at least one dose of therapy at the inner-city community health center SVR12 NR NR 7
Valencia et al (30) 2019 Original article Spain; a follow-up cohort real-life study Enrolled PWID and who consumed heroin and/or cocaine during the previous 6 months and received interferon-free HCV treatment at two low-threshold mobile harm reduction units SVR12 0.6(0.3–1.3) years of EOT Every 3–6 months 5
Young et al (13) 2017 Original article Canada; a prospective cohort study Enrolled patients achieving SVR after HCV treatment from PWID or MSM SVR12 1.5(0.6–3.2) years of SVR Every 6 months 5
Berenguer et al (58) 2019 Concise communication Spain; a compulsory prospective observational real-life cohort study Enrollment from the Madrid Coinfection Registry with HIV/HCV co-infection SVR12 NR Every 6–12 months 7
Huang et al (16) 2019 Original article Taiwan; a retrospective cohort study (2016 05128 RINC) Enrollment from National Taiwan University Hospital among HIV-positive Taiwanese SVR12 NR NR 4

Abbreviations: NR, not reported; EOT, end of treatment; SOT, start of treatment; ETR, end of treatment response; IQR, interquartile range; HBV, hepatitis B virus; CKD, chronic kidney disease; OAT, opioid agonist therapy; BC-HT, British Columbia Hepatitis Testers Cohort; AURIC, Austrian Ribavirin/Interferon-free Cohort; VIDC, Vancouver Infectious Diseases Centre; ASW, Ambulatorium Suchthilfe Wien.

Attainment of SVR time-point

Median (min-max) study follow-up.

The demographic and clinical characteristics of the studies are presented in Supplementary Table 1. A total of 27,061 patients achieved SVR following DAAs therapy, with 15,307 (62.7%) being males, 12,169 (82.9%) Caucasian, 6,925 (67.3%) treatment-naïve, 18,147 (70.6%) HCV genotype 1, and 5,792 (28.4%) with cirrhosis. The median age of the study population was 50 years (range, 34–72).

Five studies evaluated two distinct subgroups of high-risk HCV mono-infected and HIV/HCV coinfected patients, and were also included in two analysis groups14, 21, 2729. Ultimately, there were 43 studies included in the analysis. Within the HCV low- and high-risk HCV mono-infection and HIV/HCV coinfection groups, 14/16 (87.5%), 16/19 (84.2%) and 5/8 (62.5%), respectively, were considered high-quality (NOS score≥6). For the low-risk and high-risk HCV mono-infection population groups, funnel plots appeared symmetrical indicating no overt evidence of significant publication bias (Supplementary Figure 1A, B). However, there was significant publication bias in the HIV/HCV coinfection population group, perhaps due to the small number of studies included. Furthermore, an unexpected shape was observed in the funnel plots and the Egger’s test (P < 0.01) (Supplementary Figure 1C).

Low-risk HCV mono-infection population

Sixteen studies were found evaluating the risk of HCV recurrence in low-risk HCV mono-infected patients23, 3044. The recurrence rates per 1000 PYFU and their corresponding 95% CI were calculated for each study and are presented in Table 2. The median follow-up time post-SVR was 21 months (interquartile range, 16–28). Of the included studies, 13 had at least one HCV recurrence. Among those, 10 used genotyping or sequencing to determine recurrence type, 1 relied on author judgment/terminology, and 2 did not classify the recurrence.

Table 2.

HCV Recurrence and Rate of Recurrence in Included Studies

Study Number With SVR Avg. Follow-up Post-SVR (Total PYFU Post-SVR) Method Recurrences Recurrence Rate per 1000 PYFU (95% CI)
Late Relapse (Confirmed)a Reinfection (Confirmed)b Totalc
Low-risk HCV mono-infected population
Carey et al 2013 41 0.75(29.88) Terminology 2(0) 0 2 66.93(0.99–201.74)
Rutter et al 2013 103 1.75(175.67) Sequence 2(2) 0 2 11.38(0.17–34.31)
Zeuzem et al 2015 1054 0.75(780.38) Sequence 4(4) 1(1) 5 6.41(1.78–13.51)
Howe et al 2015 696 3.40(2227.20) Sequence 3(0) 1(1) 4 1.80(0.38–4.09)
Lawitz et al 2016 5433 1.23(6749.26) Sequence 6(6) 12(12) 19 2.82(1.68–4.24)
Muir et al 2016 1067 1.50(1599.00) - - - 1 0.63(0.00–2.69)
Bourlière et al 2017 1444 1.90(2743.53) Sequence 1(1) 7(7) 8 2.92(1.19–5.35)
Jacobson et al 2018 2348 2.43(5034.37) Sequence 1(1) 6(6) 7 1.39(0.52–2.65)
Hayashi et al 2018 413 1.79(737.46) Sequence 4(4) 0 4 5.42(1.14–12.35)
Hayashi K et al 2018 54 6.00(319.67) Sequence 1(1) 0 1 3.13(0.00–13.44)
Reddy et al 2018 1097 2.38(3360.44) Genotype 12(0) 1(1) 13 3.87(2.01–6.30)
Zoulim et al 2018 200 2.98(596.67) - 0 0 0 0.00(0.00–8.09)
Mangia et al 2018 1245 1.48(1842.85) Sequence 0 1(1) 1 0.54(0.00–2.33)
Kozbial et al 2018 551 1.37(615.29) - 0 0 0 0.00(0.00–2.79)
Flisiak et al 2018 200 1.75(350.00) - 0 0 0 0.00(0.00–4.91)
Manoj et al 2018 71 1.25(67.25) - - - 2 29.74(0.44–89.64)
High-risk HCV mono-infected population
Dore et al 2017 199 2.29(385.20) Sequence 0 5(0) 5 12.98(3.61–27.38)
Ingiliz et al 2018 1960 0.54(1141.00) Genotype 0 32(14) 32 28.05(19.10–38.68)
Cuadrado et al 2018 61 1.75(107.00) - 0 0 0 0.00(0.00–16.06)
Bouscaillou et al 2018 169 1.00(165.75) Risk factors 0 2(0) 2 12.07(0.18–36.37)
Schubert et al 2018 178 1.08(192.00) Risk factors 0 11(0) 11 57.29(27.71–96.89)
Midgard et al 2018 83 0.58(50.25) Genotype 0 1(0) 1 19.90(0.00–85.50)
Bhandari et al 2020 48 1.08(52.00) Terminology 0 21(0) 21 403.85(247.59–597.05)
Rahman et al 2019 48 0.50(24.00) Genotype 0 1(1) 1 41.67(0.00–179.02)
Holeksa et al 2019 243 1.96(474.00) Risk factors 0 4(2) 4 8.44(1.78–19.21)
Marco et al 2019 30 3.58(82.90) Risk factors 0 3(0) 3 36.19(4.40–91.77)
Cunningham et al 2020 177 1.55(209.75) Sequence 0 8(8) 8 38.14(15.53–69.94)
Akiyama et al 2020 141 1.41(210.75) Sequence 0 3(2) 3 14.23(1.73–36.10)
Chan et al 2020 114 1.37(170) - - - 18 105.88(61.96–161.11)
Habchi et al 2020 232 NR(306.75) Risk factors 0 30(0) 30 97.80(65.65–136.21)
Alimohammadi et al 2018 183 NR(304.92) - 0 0 0 0.00(0.00–5.64)
Rossi et al 2018 3711 NR(2388.36) Risk factors 0 27(0) 27 11.30(7.40–16.01)
Wyles et al 2018 89 1.85(190.60) Genotype 0 1(0) 1 5.25(0.00–22.54)
Selfridge et al 2019 198 NR(200.00) Genotype 0 3(0) 3 15.00(1.82–38.04)
Valencia et al 2019 68 NR(29.50) Genotype 0 4(4) 4 135.59(28.59–308.62)
HIV/HCV coinfected population
Alimohammadi et al 2018 24 NR(40.08) - 0 0 0 0.00(0.00–42.89)
Rossi et al 2018 403 NR(378.44) Risk factors 0 13(0) 13 34.35(17.87–55.91)
Wyles et al 2018 116 2.29(287.50) Genotype 0 1(1) 1 3.48(0.00–14.94)
Selfridge et al 2019 51 NR(53.00) Genotype 0 5(0) 5 94.34(26.24–198.99)
Valencia et al 2019 53 NR(41.25) Genotype 0 6(5) 6 145.45(48.07–289.67)
Young et al 2017 51 NR(76.25) - 0 0 0 0.00(0.00–22.54)
Berenguer et al 2019 2359 NR(3546.00) Genotype 0 17(10) 17 4.79(2.75–7.38)
Huang et al 2019 55 NR(38.10) Genotype 0 4(2) 4 104.99(22.14,238.96)

Entries marked with a dash gave no indication whether the recurrence was a late relapse or a reinfection.

Abbreviation: NR, not reported.

a

Number of suspected late relapses (no. confirmed by genotyping or sequencing).

b

Number of suspected reinfections (no. confirmed by genotyping or sequencing).

c

Total number of late relapses and reinfections.

Sixty-nine HCV recurrences were observed in a total of 16,017 patients. Overall, recurrence rates varied from 0.00/1000 PYFU to 66.93/1000 PYFU among the included studies (Table 2). Consequently, the pooled estimate for the recurrence rate was 0.89/1000 PYFU (95% CI, 0.16–2.03) based on a random effects model and a substantial level of heterogeneity was observed (I2 = 61%) (Table 3).

Table 3.

Rate of HCV Recurrence post-SVR following DAAs therapy

Studies Subgroup No. of Studies Pooled Estimate of Recurrence/1000 PYFU (95% CI) Heterogeneity (I2; P Value)
Low-risk HCV mono-infected population
All studies All 16 0.89(0.16–2.03) 61%; <0.01
Sensitivity analysis High-quality (NOS≥6) 14 1.22(0.45–2.26) 54%; <0.01
Subgroups Recurrence in prospective cohorts 6 1.31(0.61–2.20) 41%; 0.13
Recurrence in RCTs 10 0.76(0.00–2.64) 68%; <0.01
Late relapse 14 0.32(0.00–1.40) 73%; <0.01
Reinfection 14 0.06 (0.00–0.32) 0%; 0.57
High-risk HCV mono-infected population
All studies All 19 29.37(15.54–46.91) 90%; <0.01
Sensitivity analysis High-quality (NOS≥6) 16 28.68(13.21–49.22) 91%; <0.01
Subgroups Recurrence in prospective cohorts 8 51.74(16.70–102.78) 89%; <0.01
Recurrence in RCTs 4 14.21(3.53–30.60) 59%; 0.06
Recurrence in retrospective cohorts 7 26.83(7.10–57.70) 93%; <0.01
All PWID studies 15 19.65(8.50–34.48) 85%; <0.01
All prisoner studies 4 85.89(3.52–258.56) 94%; <0.01
Late relapse 18 0.00(0.00–0.00) 0%; 1.00
Reinfection 18 25.82(13.08–42.13) 89%; <0.01
HIV/HCV coinfected population
All studies All 8 23.25(4.24–53.39) 88%; <0.01
Sensitivity analysis High-quality (NOS≥6) 5 13.66(0.48–38.64) 87%; <0.01
Subgroups Recurrence in prospective cohorts 4 9.33(0.00–34.55) 83%; <0.01
Recurrence in retrospective cohorts 4 43.34(8.44–99.15) 66%; 0.03
Late relapse 8 0.00(0.00–0.00) 0%; 0.76
Reinfection 8 23.25(4.24–53.39) 88%; <0.01

Abbreviations: NO, number; RCTs, randomized controlled trials; PWID, persons who inject drugs.

Forest Plots of recurrence rates can be found in the Supplementary Appendix (Supplementary Figure. 2A, 2B and 2C).

Of the included 69 HCV recurrences, 36 were assessed as late relapse and 29 were reinfection, while the recurrence type was not classified in the remaining four patients. The pooled estimate was 0.32/1000 PYFU (95% CI, 0.00–1.40) for late relapse, and 0.06/1000 PYFU (95% CI, 0.00–0.32) for reinfection (Table 3).

High-risk HCV mono-infected population

Nineteen studies were identified assessing recurrence in high-risk patients who achieved SVR following DAAs therapy14, 15, 21, 2729, 4557. The median follow-up time post-SVR was 17 months (interquartile range, 9–21). Of those studies, four evaluated the risk in prisoners15, 49, 53, 56, one in mono-infected MSM or PWID48, and the other primarily in PWID. Among those, 17 studies reported at least one HCV recurrence; 9 out of 17 used genotyping or sequencing to determine recurrence type, 7 relied on author judgment/terminology/risk factors, and 1 did not classify the recurrence.

One hundred and seventy-four HCV recurrences were observed in a total of 7,932 patients. In total, the recurrence rate varied from 0.00/1000 PYFU to 403.85/1000 PYFU among the studies. The pooled recurrence rate estimate was 29.37/1000 PYFU (95% CI, 15.54–46.91; I2 = 90%) (Table 3). After adjustment for study follow-up duration, meta-regression analysis indicated that this population experienced a 10.79% increased risk of HCV recurrence (relative risk [RR] 1.1079, 95% CI, 1.0324–1.1890; P = 0.0044) compared to the low-risk HCV mono-infected population (Supplementary Table 2).

Of the included 174 HCV recurrences, 156 were reinfection and none were late relapse; the recurrence type was not classified in the remaining 18 patients. In regard to recurrence type, it appears HCV recurrence was driven by reinfection (25.82/1000 PYFU, 95% CI, 13.08–42.13) rather than late relapse (Table 3).

HIV/HCV co-infection population

Eight articles assessed HCV recurrence among HIV/HCV coinfected patients13, 16, 21, 2729, 58. Of those, one was carried out predominantly in MSM16, one in targeted PWID 58, and the remaining studies reported mixed populations. Four studies were retrospective cohorts, while the remainder were prospective cohorts. The median follow-up time post-SVR was 16 months (interquartile range, 11–21). Of the included studies, six studies reported at least one recurrence.

In summary, 46 recurrences were observed in a total of 3,112 patients. The pooled recurrence rate was 23.25/1000 PYFU (95% CI, 4.24–53.39) (Table 3) and the recurrence rates in individual studies ranged from 0.00/1000 PYFU to 145.45/1000 PYFU, although there was a considerable level of heterogeneity. As in the high-risk HCV mono-infection group, HIV/HCV co-infection was associated with an increased risk of HCV recurrence compared to the low-risk HCV mono-infection population (RR 1.0960, 95% CI, 1.0001–1.2010, P = 0.0498) (Supplementary Table 2). However, no significant difference was observed between the high-risk HCV mono-infected population and HIV/HCV coinfected population (RR 0.9893, 95% CI, 0.9056–1.0807, P = 0.8106).

By recurrence type, the pooled estimates for late relapse and reinfection were 0.00/1000 PYFU (95% CI, 0.00–0.00) and 23.25/1000 PYFU (95% CI, 4.24–53.39), respectively (Table 3). Furthermore, when combining the HIV/HCV coinfected patients with high-risk HCV mono-infected patients, the estimated reinfection risk among PWID following DAAs-induced SVR was 18.31/1000 PYFU (95% CI, 9.70–29.16; I2 = 89%) (Supplementary Figure 3).

HCV recurrence following DAAs therapy versus IFN therapy

A previous study reported HCV recurrence following SVR after treatment with IFN-based or DAAs-based therapies11. Of the included studies, there were 58 IFN-based and 3 DAAs-based studies. Using these data, we then demonstrated that recurrence rates following IFN-based therapy were 2.00/1000 PYFU (95% CI, 0.73–3.69), 22.09/1000 PYFU (95% CI, 12.90–33.23) and 30.89/1000 PYFU (95% CI, 0.00–123.23) in low-risk HCV mono-infected, high-risk HCV mono-infected and HIV/HCV coinfected populations, respectively (Supplementary Figure 4A, B and C).

In a meta-regression analysis after adjusting for age and study follow-up covariates, DAAs therapy was not associated with lower HCV recurrence in the low-risk HCV mono-infected population (RR 0.9893, 95% CI 0.9520–1.0280, P = 0.5813), high-risk HCV mono-infected population (RR 0.9924, 95% CI 0.9205–1.0700, P = 0.8439) and HIV/HCV coinfected population (RR 0.8784, 95% CI, 0.7354–1.0493, P = 0.1528) when compared to IFN therapy (Table 4). After adjusting for age, study follow-up was negatively correlated with HCV recurrence following HCV “cure” and the recurrence rate was lower with longer follow-up. The partial correlation coefficients were −0.296, −0.449 and −0.822 in the low-risk HCV mono-infected, high-risk HCV mono-infected and HIV/HCV coinfected populations, respectively (P < 0.05) (Figure 2A, B and C).

Table 4.

The association of DAAs vs IFN-induced SVR with HCV recurrence by meta-regression analysis

Variables Univariate analysis Multivariate analysis

RR 95% CI P value aRR 95% CI P value
Low-risk HCV mono-infected population
Treatment
IFN 1.0000 1.0000
DAAs 0.9915 0.9679,1.0157 0.4888 0.9893 0.9520,1.0280 0.5813
Average follow-up, years 0.9950 0.9900,1.0002 0.0586 0.9946 0.9885,1.0009 0.0909
Average age, year 0.9990 0.9973,1.0006 0.2293 0.9989 0.9967,1.0012 0.3559
High-risk HCV mono-infected population
Treatment
IFN 1.0000 1.0000
DAAs 1.0107 0.9371,1.0900 0.7834 0.9924 0.9205,1.0700 0.8439
Average follow-up, years 0.9800 0.9513,1.0096 0.1844 0.9572 0.9256,0.9990 0.0108
Average age, year 0.9971 0.9935,1.0006 0.1059 0.9937 0.9892,0.9982 0.0063
HIV/HCV coinfected population
Treatment
IFN 1.0000 1.0000
DAAs 0.9921 0.8255,1.1924 0.9328 0.8784 0.7354,1.0493 0.1528
Average follow-up, years 0.9227 0.8728,0.9755 0.0046 0.8761 0.8419,0.9117 <0.0001
Average age, year 0.9957 0.9839,1.0075 0.4751 0.9948 0.9854,1.0044 0.3740

Abbreviations: RR, relative risk; aRR, adjusted relative risk.

Figure 2. HCV recurrence incidence rates per 1000 person-years.

Figure 2.

HCV recurrence rates by average follow-up duration in (A) low-risk HCV mono-infected population; (B) high-risk HCV mono-infected population, and (C) HIV/HCV coinfected populations. HCV recurrence rates were significantly associated with average follow-up duration in three populations of differing risk levels (A, B, C). Partial r and P values were obtained after adjustment for age.

DISCUSSION

The widespread availability of pan-genotypic combination DAAs regimens has provided major individual and population level benefits for chronic hepatitis C infection5961. The favorable effects of HCV antiviral therapy have been clearly demonstrated in patients who achieve SVR, in whom liver-related and all-cause mortality are significantly reduced9, 62. However, SVR does not confer lifelong protection against reinfection with HCV. Furthermore, there is minimal data available describing the long-term durability of DAAs-induced SVR, particularly in patients with ongoing risk factors for transmission. In this paper, our findings reflect that the substantial majority of patients who achieved SVR following DAAs treatment maintain undetectable HCV RNA levels. Although there is a subgroup of patients that are at higher risk for HCV recurrence, the risk of recurrence was still low in these populations, suggesting that DAAs-induced SVR is durable11.

The current study demonstrates that HCV recurrence was 0.89/1000 PYFU in low-risk HCV mono-infected patients but increased to 29.37/100 PYFU and 23.25/1000 PYFU in the high-risk HCV mono-infected and HIV/HCV coinfected populations, respectively. In addition, we calculated that the high-risk HCV mono-infected and HIV/HCV coinfected populations experienced a 10.79% and 9.60% increased risk of HCV recurrence, respectively, compared to the low-risk HCV mono-infected population. Notably, these recurrences were largely driven by reinfection rather than late relapse. Rossi et al previously reported that reinfection rates were higher among PWID than in low-risk HCV mono-infected patients following successful DAAs therapy likely due to the persistent risk of exposure21. Together these data re-emphasize the need for education and preventive measures in individuals with ongoing high-risk behaviors, as well as the need for ongoing HCV monitoring in these individuals63.

In our study, the estimated reinfection risk among PWID post-DAAs-induced SVR was 18.31/1000 PYFU (95% CI, 9.70–29.16). This estimate is lower than that reported in previous systematic reviews evaluating the rate of HCV reinfection among PWID (19 to 62 per 1000 person-years)24, 64, 65. Previous systematic reviews were limited by the small number of included studies and lack of data on HCV reinfection post-SVR in the DAAs era. Furthermore, those studies examined the rate of HCV reinfection at the end of treatment, while in our analysis, studies with less than six months of follow-up post-SVR were excluded. As a result, our study provides the most comprehensive review of long-term HCV recurrence post- DAAs-induced SVR among low- and high-risk HCV mono-infected and HIV/HCV coinfected population groups.

Prior to the development of all-oral DAAs regimens, IFN-based therapy was the standard of care for the treatment of HCV. In contrast to DAAs that target specific HCV proteins involved in viral replication, the mechanism of action of IFN was through broad antiviral effects and immune modulation36. Owing to the high potency of combination DAAs regimens, treatment is not only more effective (>95% SVR), but treatment durations are considerably shorter (8–12 weeks compared to 24–48 weeks of IFN plus RBV). Due to differences in the mechanism of action and potency between IFN plus RBV and DAAs, the timing of SVR assessment has also changed from 24 weeks after cessation of therapy with IFN-based therapy (SVR24), to 12 weeks post- cessation of therapy with DAAs (SVR12). Therefore, the durability of SVR, with respect to late relapse and reinfection due to high-risk behaviors, has been of concern in patients receiving DAAs. Our integrated comprehensive analysis showed that there was no evidence for differential recurrence risks after achieving SVR with DAAs therapy compared to IFN-based therapy overall and among the three sub-populations. Consequently, SVR achieved with all-oral DAAs is durable, and importantly, as durable as that obtained through IFN-based therapy. Furthermore, due to the low risk of HCV recurrence even in the high risk HCV mono-infection and HIV/HCV co-infection populations, there would appear to be no reason to withhold or defer DAAs therapy in patients who remain at risk for reinfection6670.

Interestingly, we also found that the lower rate of HCV recurrence post-SVR following antiviral treatments (IFN-based and DAAs) were associated with longer follow-up duration. By inference, the recurrence risk is greatest soon after achieving SVR. Another explanation may be loss to follow-up or bias resulting from the differences in follow-up duration as there were few PYFU among those with early HCV recurrence post-SVR. In the future, studies to determine the rate of HCV recurrence will require sufficient follow-up duration and strategies to enhance adherence to ensure there are adequate person-years of post-SVR follow-up to minimize the potential for bias.

The advent and widespread use of DAAs with high SVR rates and low adverse events has been one of the major advances in clinical medicine in recent decades and makes it possible to eliminate hepatitis C and significantly reduce HCV-related morbidity and mortality5961, 71. It provides an opportunity for broad treatment up-scaling thereby increasing the potential to meet the WHO 2030 targets. However, in order to meet both the reduction in incidence and mortality targets, all patients, including individuals who may be high-risk for HCV recurrence, need to be treated. This is particularly important considering the fact that the majority of new HCV infections are acquired in PWID72, which remains an ongoing challenge towards achieving global HCV elimination. However, the high prevalence and incidence in these high-risk groups, as well as our data demonstrating a low HCV recurrence rate, highlights the critical importance of treating these individuals to restrict the HCV transmission pool. It also encourages the adoption of additional strategies to prevent HCV reinfection and manage high-risk and HIV/HCV coinfected populations. This should occur at the individual level as well as at the state and federal level if the WHO viral hepatitis targets are to be met73, 74.

The strength of our systematic review is that it is the first quantitative and comprehensive analysis for HCV recurrence in the DAAs era accounting for populations of different risk levels. However, there are several limitations of this study. First, the mean follow-up period for 36/44 (82%) studies was relatively short (< 26 months). Longer follow-up durations would be more appropriate as one previous study evaluating the incidence of late relapse in low-risk HCV mono-infected patients with genotype 1b who achieved SVR with daclatasvir and asunaprevir36, found that late relapse was a rare event that occurred within 26 months after SVR. Since the follow-up duration contributes to PYFU, a study with a short follow-up period also results in wide CIs for the risk estimate of HCV recurrence. In addition, it possibly leads to a miscalculation of the true recurrence rate. Second, complete records on patients who dropped out of long-term follow-up were not available and it is possible that people lost to follow-up and not included in the studies also experienced recurrence events. This would lead to potential selection bias which limits interpretation of the results. Long-term follow-up adherence might also be potentially important when considering late relapse.

Although there is a low likelihood of viral relapse after SVR particularly in high-risk populations17, 75, HCV sequencing should ideally be performed in individuals with late recurrent viremia, to distinguish between HCV reinfection and late relapse in terms of assessing recurrence type. In those studies not utilizing sequencing methods but rather genotyping or author judgment, bias may have been introduced by the tendency to classify either late relapse or reinfection. Therefore, the HCV recurrence risks calculated may not be accurate. Finally, our study did not include patients who had acute HCV or spontaneously cleared acute HCV. There is evidence demonstrating that HCV recurrence can occur not only in the chronic stage but also in acute HCV or after spontaneous clearance76, 77. Since these patients are often asymptomatic, this is a difficult cohort to amass, and there are extremely limited data available. As a result, if these patients were captured and followed, the calculated HCV recurrence rates may have been higher.

In conclusion, the risk of HCV recurrence following SVR achieved with all-oral DAAs therapy is low. Although recurrence rates in high-risk HCV mono-infected and HIV/HCV coinfected populations are significantly higher than those in low-risk populations, the rates are still low. These data demonstrate that SVR rates achieved with all-oral DAAs therapy is comparable to that observed with IFN therapy. Given these data, we believe the ambitious HCV elimination targets set by the WHO are achievable and that high-risk patients should not be excluded from treatment algorithms and government policies if these targets are to be met.

Supplementary Material

sm

Key points.

  • There is limited data regarding the long-term durability of SVR following DAAs therapy is available.

  • The present study summarizes the evidence on HCV recurrence (late relapse and reinfection) post-SVR following DAAs-based therapy between 2011 and 2020.

  • For high-risk HCV mono-infected and HIV/HCV coinfected populations, HCV recurrence after achieving SVR following DAAs therapy was driven by an increase in reinfection when compared to the low-risk HCV mono-infected population.

Funding statement:

This study was supported by the National Natural Science Foundation of China (No. 81703273 (PH), 81703321 (SY), 81871661 (WL)), Natural Science Foundation of Jiangsu Province (BK20171054) (PH), Natural Science Foundation of Yunnan Province (2019FA005) (XSX, PH), National Institutes of Health (NIH) /NIAID 1R01AI155140 (RTC and WL), and NIH AI136715 (RTC), AI082630 (RTC), DK108370 (RTC).

Abbreviations:

HCV

hepatitis C virus

WHO

World Health Organization

HCC

hepatocellular carcinoma

IFN

interferon

DAAs

direct-acting antivirals

SVR

sustained virological response

PWID

persons who inject drugs

MSM

men who have sex with men

HIV

human immunodeficiency virus

RBV

ribavirin

PYFU

person-years of follow-up

NOS

Newcastle-Ottawa Scale

CI

confidence interval

Footnotes

Conflict of interest declaration: All authors disclose no conflicts of interest.

REFERENCES

  • 1.Organization World Health. Global hepatitis report, 2017. 2017. [Google Scholar]
  • 2.Seeff LB Natural history of chronic hepatitis C. Hepatology 2002;36:S35–46. [DOI] [PubMed] [Google Scholar]
  • 3.Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211–221. [DOI] [PubMed] [Google Scholar]
  • 4.Bansal S, Singal AK, McGuire BM, Anand BS Impact of all oral anti-hepatitis C virus therapy: A meta-analysis. World J Hepatol 2015;7:806–813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Organization World Health. Global health sector strategy on viral hepatitis 2016–2021. 2016. [Google Scholar]
  • 6.Morisco F, Granata R, Stroffolini T, et al. Sustained virological response: a milestone in the treatment of chronic hepatitis C. World J Gastroenterol 2013;19:2793–2798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Lindsay KL Introduction to therapy of hepatitis C. Hepatology 2002;36:S114–120. [DOI] [PubMed] [Google Scholar]
  • 8.Ghany MG, Strader DB, Thomas DL, Seeff LB Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Pearlman BL, Traub N Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011;52:889–900. [DOI] [PubMed] [Google Scholar]
  • 10.Cacoub P, Desbois AC, Comarmond C, Saadoun D Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut 2018;67:2025–2034. [DOI] [PubMed] [Google Scholar]
  • 11.Simmons B, Saleem J, Hill A, Riley RD, Cooke GS Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis 2016;62:683–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Asher AK, Portillo CJ, Cooper BA, et al. Clinicians’ Views of Hepatitis C Virus Treatment Candidacy With Direct-Acting Antiviral Regimens for People Who Inject Drugs. Subst Use Misuse 2016;51:1218–1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Young J, Rossi C, Gill J, et al. Risk Factors for Hepatitis C Virus Reinfection After Sustained Virologic Response in Patients Coinfected With HIV. Clin Infect Dis 2017;64:1154–1162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Alimohammadi A, Holeksa J, Thiam A, Truong D, Conway B Real-world Efficacy of Direct-Acting Antiviral Therapy for HCV Infection Affecting People Who Inject Drugs Delivered in a Multidisciplinary Setting. Open Forum Infect Dis 2018;5:ofy120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Cuadrado A, Llerena S, Cobo C, et al. Microenvironment Eradication of Hepatitis C: A Novel Treatment Paradigm. Am J Gastroenterol 2018;113:1639–1648. [DOI] [PubMed] [Google Scholar]
  • 16.Huang MH, Chang SY, Liu CH, et al. HCV reinfections after viral clearance among HIV-positive patients with recent HCV infection in Taiwan. Liver Int 2019;39:1860–1867. [DOI] [PubMed] [Google Scholar]
  • 17.Sarrazin C, Isakov V, Svarovskaia ES, et al. Late Relapse Versus Hepatitis C Virus Reinfection in Patients With Sustained Virologic Response After Sofosbuvir-Based Therapies. Clin Infect Dis 2017;64:44–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Pineda JA, Nunez-Torres R, Tellez F, et al. Hepatitis C virus reinfection after sustained virological response in HIV-infected patients with chronic hepatitis C. J Infect 2015;71:571–577. [DOI] [PubMed] [Google Scholar]
  • 19.Midgard H, Bjoro B, Maeland A, et al. Hepatitis C reinfection after sustained virological response. J Hepatol 2016;64:1020–1026. [DOI] [PubMed] [Google Scholar]
  • 20.Ovrehus ALH, Krarup H, Birkemose I, et al. Four weeks of ledipasvir/sofosbuvir and ribavirin with or without pegylated interferon for chronic hepatitis C in non-cirrhotic people who inject drugs. A randomized trial. J Hepatol 2018;68:840–842. [DOI] [PubMed] [Google Scholar]
  • 21.Rossi C, Butt ZA, Wong S, et al. Hepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort. J Hepatol 2018;69:1007–1014. [DOI] [PubMed] [Google Scholar]
  • 22.Lawitz Eric, Poordad Fred, Kowdley Kris V, et al. A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. J Hepatol 2013;59:18–23. [DOI] [PubMed] [Google Scholar]
  • 23.Howe AY, Long J, Nickle D, et al. Long-term follow-up of patients receiving boceprevir for treatment of chronic hepatitis C. Antiviral Res 2015;113:71–78. [DOI] [PubMed] [Google Scholar]
  • 24.Hajarizadeh B, Cunningham EB, Valerio H, et al. Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: A meta-analysis. J Hepatol 2020;72:643–657. [DOI] [PubMed] [Google Scholar]
  • 25.Miller John J The Inverse of the Freeman – Tukey Double Arcsine Transformation. The American Statistician 1978;32:138–138. [Google Scholar]
  • 26.Higgins JP, Thompson SG, Deeks JJ, Altman DG Measuring inconsistency in meta-analyses. Bmj 2003;327:557–560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Wyles DL, Kang M, Matining RM, Murphy RL, Peters MG Similar Low Rates of HCV Recurrence in HCV/HIV- and HCV-Infected Participants who Achieved SVR After DAA Treatment: Interim Results From the ACTG A5320 Viral Hepatitis C Infection Long-term Cohort Study (V-HICS). Open Forum Infect Dis 2018;5:ofy103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Selfridge Marion, Cunningham Evan B, Milne Rozalyn, et al. Direct-acting antiviral treatment for hepatitis C, reinfection and mortality among people attending an inner-city community health centre in Victoria, Canada. Int J Drug Policy 2019;72:106–113. [DOI] [PubMed] [Google Scholar]
  • 29.Valencia Jorge, Alvaro-Meca Alejandro, Troya Jesús, et al. High rates of early HCV reinfection after DAA treatment in people with recent drug use attended at mobile harm reduction units. Int J Drug Policy 2019;72:181–188. [DOI] [PubMed] [Google Scholar]
  • 30.Zoulim F, Moreno C, Lee SS, et al. A 3-year follow-up study after treatment with simeprevir in combination with pegylated interferon-alpha and ribavirin for chronic hepatitis C virus infection. Virol J 2018;15:26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Rutter K, Hofer H, Beinhardt S, et al. Durability of SVR in chronic hepatitis C patients treated with peginterferon-2a/ribavirin in combination with a direct-acting anti-viral. Aliment Pharmacol Ther 2013;38:118–123. [DOI] [PubMed] [Google Scholar]
  • 32.Flisiak R, Janczewska E, Lucejko M, et al. Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir+/−dasabuvir+/−ribavirin in the AMBER, real-world experience study. J Viral Hepat 2018;25:1298–1305. [DOI] [PubMed] [Google Scholar]
  • 33.Carey I, Lee HJ, Calara J, et al. Follow-up after cessation of therapy with direct acting antivirals in hepatitis C patients-Who is at risk of late relapse? J Hepatol 2013;58:S328–S328. [Google Scholar]
  • 34.Kozbial K, Moser S, Al-Zoairy R, et al. Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment. Liver Int 2018;38:1028–1035. [DOI] [PubMed] [Google Scholar]
  • 35.Manoj Kumar, Nayak SL, Gupta E, Kataria A, Sarin SK Generic sofosbuvir-based direct-acting antivirals in hepatitis C virus-infected patients with chronic kidney disease. Liver Int 2018;38:2137–2148. [DOI] [PubMed] [Google Scholar]
  • 36.Hayashi K, Ishigami M, Ishizu Y, et al. Late relapse of hepatitis C virus in patients with sustained virological response after daclatasvir and asunaprevir therapy. J Viral Hepat 2018;25:1446–1451. [DOI] [PubMed] [Google Scholar]
  • 37.Zeuzem Stefan, Jacobson Ira M, Feld Jordan J, et al. Long-Term Efficacy of Ombitasvir/Paritaprevir/r and Dasabuvir With or Without Ribavirin in HCV Genotype 1-Infected Patients With or Without Cirrhosis. 2015. [Google Scholar]
  • 38.Bourliere Marc, Gane Edward J, Jacobson Ira, et al. Long-Term Follow Up of Patients with Chronic HCV and No or Minimal Fibrosis Shows Low Risk for Liver-Related Morbidity and Mortality After Achieving SVR with DAA-Based Therapy: Results from the Gilead SVR Registry. Hepatology 2017;66:518A–519A.28390159 [Google Scholar]
  • 39.Reddy KR, Pol S, Thuluvath PJ, et al. Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens. Liver Int 2018;38:821–833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Mangia A, Lawitz E, Gane E, et al. Long-term follow-up of patients with chronic HCV infection and compensated or decompensated cirrhosis following treatment with sofosbuvir-based regimens. J Hepatol 2018;68:S67–S68. [Google Scholar]
  • 41.Muir Andrew J, Buti Maria, Nahass Ronald, et al. Long-Term Follow-up of Patients with Chronic HCV Infection and Compensated or Decompensated Cirrhosis Following Treatment with Sofosbuvir-Based Regimens. Hepatology 2016;64:437A–438A. [Google Scholar]
  • 42.Lawitz EJ, Ruane P, Stedman C, et al. Long-term follow-up of patients with chronic HCV infection following treatment with direct acting antiviral regimens: Maintenance of SVR, persistence of resistance mutations and clinical outcomes. J Hepatol 2016;64:S612–S613. [Google Scholar]
  • 43.Jacobson Ira M, Zeuzem Stefan, Gane Edward, et al. Long-term follow-up patients with chronic HCV and F2 or F3 fibrosis after achieving SVR with DAA-based therapy:Results from the Gilead SVR registry Gastroenterology 2018;154:S1081–S1082. [Google Scholar]
  • 44.Hayashi K, Ishigami M, Yasuda S, et al. Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon-ribavirin-based therapy. Hepatol Res 2018;48:e78–e86. [DOI] [PubMed] [Google Scholar]
  • 45.Bouscaillou J, Kikvidze T, Le Pluart D, et al. HCV reinfection rates after treatment in people who inject drugs of a prospective cohort in Tbilisi. Georgia. 2018. https://az659834.vo.msecnd.net/eventsairaueprod/production-ashm-public/5b13f88f84ae43ca8b682e024bb8b838.
  • 46.Dore GJ, Grebely J, Altice F, et al. Hepatitis C Virus (HCV) Reinfection and Injecting Risk Behavior Following Elbasvir (EBR)/Grazoprevir (GZR) Treatment in Participants on Opiate Agonist Therapy (OAT): Co-STAR Part B. Hepatology 2017;66:112A–113A. [Google Scholar]
  • 47.Rahman M, Janjua NZ, Shafiq TKI, et al. Hepatitis C virus treatment in people who inject drugs (PWID) in Bangladesh. Int J Drug Policy 2019;74:69–75. [DOI] [PubMed] [Google Scholar]
  • 48.Ingiliz P, Wehmeyer M, Christensen S, et al. High incidence of HCV reinfection in MSM in the DAA era. Boston, MA. 2018. https://www.croiconference.org/abstract/high-incidence-hcv-reinfection-msm-daa-era/. [Google Scholar]
  • 49.Bhandari R, Morey S, Hamoodi A, et al. High rate of hepatitis C reinfection following antiviral treatment in the North East England Prisons. J Viral Hepat 2020;27:449–452. [DOI] [PubMed] [Google Scholar]
  • 50.Raphael Schubert, Angelika Schütz, Cornelia Schwanke, et al. Interim results of an ongoing project to eradicate HCV in people who inject drugs at risk for non-adherence to direct-acting antivirals in Vienna. 2018. [Google Scholar]
  • 51.Holeksa J, Magel T, Alimohammadi A, et al. Low rate of reinfection among a cohort of people who use drugs successfully treated for hepatitis C virus infection in Vancouver, Canada. Int J Drug Policy 2019;72:177–180. [DOI] [PubMed] [Google Scholar]
  • 52.Midgard H, Ulstein K, Backe Ø, et al. Low rate of reinfection following direct-acting antiviral HCV treatment among people with recent injecting drug use: A real-life experience. 2018.
  • 53.Marco A, Guerrero RA, Vergara M, et al. Reinfection in a large cohort of prison inmates with sustained virological response after treatment of chronic hepatitis C in Catalonia (Spain), 2002–2016. Int J Drug Policy 2019;72:189–194. [DOI] [PubMed] [Google Scholar]
  • 54.Cunningham EB, Hajarizadeh B, Amin J, et al. Reinfection following successful direct-acting antiviral therapy for hepatitis C infection among people who inject drugs. Clin Infect Dis 2021;72(8):1392–1400. [DOI] [PubMed] [Google Scholar]
  • 55.Akiyama MJ, Lipsey D, Heo M, et al. Low Hepatitis C Reinfection Following Direct-acting Antiviral Therapy Among People Who Inject Drugs on Opioid Agonist Therapy. Clin Infect Dis 2020;70:2695–2702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Chan J, Schwartz J, Kaba F, et al. Outcomes of Hepatitis C Virus Treatment in the New York City Jail Population: Successes and Challenges Facing Scale up of Care. Open Forum Infect Dis 2020;7:ofaa263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Habchi J, Thomas AM, Sprecht-Walsh S, et al. Optimizing Hepatitis C Virus (HCV) Treatment in a US Colocated HCV/Opioid Agonist Therapy Program. Open Forum Infect Dis 2020;7:ofaa310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Berenguer J, Gil-Martin A, Jarrin I, et al. Reinfection by hepatitis C virus following effective all-oral direct-acting antiviral drug therapy in HIV/hepatitis C virus coinfected individuals. Aids 2019;33:685–689. [DOI] [PubMed] [Google Scholar]
  • 59.Buggisch P, Moreno A, Isakov V, et al. Real world effectiveness of ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks in patients coinfected with HCV and HIV-1. J Hepatol 2017;66:S729–S730. [Google Scholar]
  • 60.Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015;373:2599–2607. [DOI] [PubMed] [Google Scholar]
  • 61.Naggie S, Cooper C, Saag M, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med 2015;373:705–713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Dieperink E, Pocha C, Thuras P, et al. All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C. Dig Dis Sci 2014;59:872–880. [DOI] [PubMed] [Google Scholar]
  • 63.Weir A, McLeod A, Innes H, et al. Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs. Drug Alcohol Depend 2016;165:53–60. [DOI] [PubMed] [Google Scholar]
  • 64.Aspinall EJ, Corson S, Doyle JS, et al. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis. Clin Infect Dis 2013;57 Suppl 2:S80–89. [DOI] [PubMed] [Google Scholar]
  • 65.Latham NH, Doyle JS, Palmer AY, et al. Staying hepatitis C negative: A systematic review and meta-analysis of cure and reinfection in people who inject drugs. Liver Int 2019;39:2244–2260. [DOI] [PubMed] [Google Scholar]
  • 66.Mücke MM, Herrmann E, Mücke VT, et al. Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis. Liver Int 2019;39:1652–1660. [DOI] [PubMed] [Google Scholar]
  • 67.Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, et al. Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review. Ann Intern Med 2017;166:637–648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Yang Z, Zhuang L, Yang L, et al. Efficacy and safety of peginterferon plus ribavirin for patients aged >/= 65 years with chronic hepatitis C: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2014;38:440–450. [DOI] [PubMed] [Google Scholar]
  • 69.Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965. [DOI] [PubMed] [Google Scholar]
  • 70.Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982. [DOI] [PubMed] [Google Scholar]
  • 71.Gane EJ, Schwabe C, Hyland RH, et al. Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Naive or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections. Gastroenterology 2016;151:448–456.e441. [DOI] [PubMed] [Google Scholar]
  • 72.Martinello M, Hajarizadeh B, Grebely J, Dore GJ, Matthews GV HCV Cure and Reinfection Among People With HIV/HCV Coinfection and People Who Inject Drugs. Curr HIV/AIDS Rep 2017;14:110–121. [DOI] [PubMed] [Google Scholar]
  • 73.Grebely J, Dore GJ, Morin S, Rockstroh JK, Klein MB Elimination of HCV as a public health concern among people who inject drugs by 2030 - What will it take to get there? J Int AIDS Soc 2017;20:22146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Lombardi A, Mondelli MU Hepatitis C: Is eradication possible? Liver Int 2019;39:416–426. [DOI] [PubMed] [Google Scholar]
  • 75.Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593–1601. [DOI] [PubMed] [Google Scholar]
  • 76.Sacks-Davis R, McBryde E, Grebely J, Hellard M, Vickerman P Many hepatitis C reinfections that spontaneously clear may be undetected: Markov-chain Monte Carlo analysis of observational study data. J R Soc Interface 2015;12:20141197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Grebely J, Pham ST, Matthews GV, et al. Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection. Hepatology 2012;55:1058–1069. [DOI] [PMC free article] [PubMed] [Google Scholar]

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