High SVR12 With 8-Week Course of Direct-Acting Antivirals in Adolescents and Children With Chronic Hepatitis C: A Comprehensive Analysis

Direct-acting antiviral (DAA) treatment for 8 weeks has a sustained virological response rate in adults with chronic hepatitis C. We have conducted a systematic review and meta-analysis to compare the efficacy and safety of the 8-week vs. 12/24-week DAA treatment in adolescents and children with CHC. The PubMed, Web of Science, and Cochrane databases were searched for the relevant articles from January 1, 2017 to August 28, 2020 and further screened for literature reviews on April 1, 2021. Pool proportions with 95% CIs for SVR12 were summarized with fixed/random effects models using Freeman–Tukey double arcsine transformation. Subgroup analysis was used to explore the source of heterogeneity. Thirty-six relevant publications were identified. For adolescents aged 12–17 years old, the pooled SVR12 and AE rate were 99.4% (95% CI: 98.7–99.9) and 34.7% (95% CI: 31.9–37.6). No one discontinued treatment due to drug intolerance. In addition, the SVR12 adolescents treated for 12 and 8/24 weeks were 99.3% (95% CI: 98.4–99.9) and 100%, respectively. The pooled SVR12 rate, AEs, and SAEs for children younger than 12 years were 98.9% (95% CI: 97.3–99.8), 51.6% (95% CI: 47.0–56.2), and 1.1% (95% CI: 0.4–2.5), respectively. The most common AE was fatigue (28.4%). The SVR12 was 98.8% (95% CI: 97.1–99.8) and 100% for the pediatric patients treated for 12 weeks and 8/24 weeks, respectively. Taken together, DAAs are generally effective against CHC and well-tolerated by the adolescents and children. A treatment duration of 8 weeks is equally effective and safe as 12/24 weeks in this demographic group.

Vertical HCV infection is cleared spontaneously without treatment in 20% of the pediatric patients, while the remaining 80% develop chronic infection in the first 4 years of life that usually persists into adulthood (4)(5)(6). Early diagnosis and treatment at younger age can reduce the prevalence of chronic infection in adulthood, and therefore reduce the global burden of HCV (7). However, although 5.5 million people with chronic HCV have been treated so far, most of these patients are adults that received the less effective interferon-based regimens (2).
The Food and Drug Administration (FDA) approved supplemental administration of sofosbuvir (SOF) and a combination of sofosbuvir and ledipasvir (SOF+LDV) in April 2017 to treat HCV in adolescents aged 12-17 years (8). In addition, several single-arm clinical trials conducted in the last 2 years have shown that DAAs are highly effective in pediatric CHC patients aged 6-12 years (9,10). However, most of these studies have only analyzed the efficacy of DAAs on specific pediatric patient populations, such as those infected with HCV genotype 4 (GT) (11,12), or the treatment experienced (TE) or treatment-naïve (TN) patients (13). The efficacy of short-duration (8 weeks) DAA treatment in adolescents and children with HCV infection has not been summarized so far.
The aim of this study was to comprehensively evaluate the efficacy and safety of 8-week vs. 12/24-week DAA regimens in adolescents and children with HCV infection using data from published studies. Our findings provide valuable information for medical professionals and researchers.

MATERIALS AND METHODS
This systematic review and meta-analysis was conducted according to the preferred reporting items for systematic review and meta-analyses (PRISMA) statement (Supplementary Table 1) (14).
The exclusion criteria of the studies were as follows: (i) co-infection with HBV or HIV, (ii) evidence of HCC or other malignancy, (iii) history of solid organ or bone marrow transplantation, (iv) decompensated liver disease or chronic liver disease of a non-HCV etiology, (v) review, case report, or articles with >10 subjects, and (vi) not treated with any DAA-containing regimens.

Study Selection
The duplicate studies were first eliminated using Endnote software, and the unrelated studies were excluded by browsing through the titles and abstracts. Studies with only adult subjects or lacking DAAs in the treatment regimens were excluded, and those reporting on the efficacy or safety of DAA treatment in children were retained. The bibliographies of the most recent relevant literature reviews were manually inspected to obtain additional articles. To avoid selection bias caused by one person, two reviewers (Mr. Fu and Miss Yue) evaluated all abstracts and selected the relevant studies for full-text reading. Any disagreement was resolved by consensus among all authors.

Research Outcomes
The primary outcome was the efficacy of DAA regimens in adolescents and children, which was defined as the percentage of patients with SVR12 [HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after cessation of therapy]. The SVR12 in this meta-analysis was the intention-to-treat (ITT) SVR12. The second outcome was the percentage of patients with adverse events (AEs) and serious AEs (SAEs). The AEs were defined as any unfavorable medical event reported by patients or any aberrations observed by the clinicians from the baseline laboratory indices after administration of the first dose until 30 days after the last dose. Common AEs included fatigue, nausea, and so on. The SAEs were defined as any event causing disability, congenital malformation, or death (8,(15)(16)(17). The worsening of laboratory test values from baseline was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (18). The safety of DAA regimen for HCVinfected patients was evaluated by the rate of drug-related AEs, SAEs, discontinuation, and laboratory abnormalities (19).

Data Extraction and Quality Evaluation
All relevant data including SVR12 (the primary endpoints of interest), side effects, study characteristics (e.g., study author, publication date, study type, and study sites), patient characteristics at baseline (e.g., age, sex rate, genotype, and Frontiers in Medicine | www.frontiersin.org treatment regimen/duration), and possible factors that affect the outcomes of treatment were extracted from the articles. The study subjects were divided into the adolescents (12-17 years) and children (<12 years of age) groups.
All studies were assessed for methodological quality using the tool of Review Manager 5.2. The items of evaluation refer to a National Institutes of Health quality assessment tool: the tool for "Before-After (Pre-Post) Studies With No Control Group" (https://www.nhlbi.nih.gov/health-topics/study-qualityassessment-tools) (Supplementary Table 3). Each criterion was graded as "yes, " "no, " or "unclear, " which corresponded to "low bias risk, " "high bias risk, " and "unclear risk of bias, " respectively.

Statistical Analyses
R x64-3.6.1 software (The R Foundation for Statistical Computing) was used for the meta-analysis. Pool proportions with 95% CIs for SVR were summarized with fixed effects models using Freeman-Tukey double arcsine transformation (20). Fixed/random effects models were used in all analyses, and statistical heterogeneity was calculated with the I 2 method and subgroup differences using the Q-test. I 2 was calculated as follows: I 2 (%) = 100 × (Q − df)/Q, where Q is Cochrane's heterogeneity statistic and df indicates the degree of freedom. Negative values for I 2 were set to zero, and an I 2 ≥ 50% was considered to have substantial heterogeneity. Publication bias was analyzed by Funnel plots. P < 0.05 was considered statistically significant.

RESULTS
A total of 741, 1,344, and 188 studies were initially identified in the PubMed, Web of Science, and Cochrane Library databases, respectively, of which 444 duplicate articles were excluded. After screening the titles and abstracts, 1,767 articles were further excluded. After including 21 additional articles from manual search of the reference lists, a total of 73 papers were eligible for full-text screening, of which 45 were excluded for incomplete data and/or inappropriate age groups (patients aged ≥18 years) and 7 for patients with co-morbidities. Another eight articles were included after the later literature search. Finally, 36 articles were included for further review, except for one that included both children and adolescents (Figure 1).

Studies and Patients' Characteristics
The main characteristics of the patients and studies are summarized in Table 1. A total of 28 studies were included, of which 18 were from Egypt, 7 from the United States, 4 from India, and 5 from multiple or other countries. All studies were observational, and 14 were multi-center studies. Except for three studies that did not specify the age groups, a total of 1,718 patients (1,253 adolescents and 465 children) were included in the studies, of which 792 were infected with HCV GT4, 545 with HCV GT1, 156 with GT3, 43 with HCV GT2, 1 with HCV GT5, and 213 with unknown GTs. Apart form 267 patients with unavailable treatment history, 1,216 were TN and 272 were TE. The majority of the patients (59%, 951/1,612) were males.
The methodological quality of each study is shown in Supplementary Figures 1, 2. The quality assessment criteria according to the National Institute of Health quality assessment tools are listed in Supplementary Table 3 (https://www.nhlbi.nih .gov/health-topics/study-quality-assessment-tools). As shown in Supplementary Figure 2, most items had good level of research quality except for Q5, which was the result of patient specificity.

Efficacy Analysis of DAAs in Children With CHC
A total of nine studies including 465 pediatric patients were included for SVR12 evaluation, and the fixed-effect model showed that the pooled SVR12 rate was 98.9% (454/465, 95% CI: 97.3-99.8) (10, 11, 13, 17, 21, 24-26, 37, 46). There was little heterogeneity among these studies (I 2 = 35%, P = 0.13) (Figure 2B), and no significant publication bias was observed as per the funnel plot (t = −0.68, P = 0.519) (Supplementary Figure 3B). Eight of these studies reported the efficacy of 12-week treatment, two studies reported the efficacy of 8-week treatment, and only one study observed the outcomes   Figure 4B). No distinct heterogeneity was observed among these groups (P = 0.676). Moreover, the pooled SVR12 rate for children with CHC was independent of HCV genotypes, treatment history, and treatment regimens (Supplementary Figures 6B-8B).

Safety Analysis of DAAs in Children With CHC
As shown in Table 3, the AE rates in pediatric patients treated with DAAs for 8, 12, and 24 weeks were 57.8, 45.1, and 98.7%, respectively (Supplementary Figure 5B)

DISCUSSION
Compared to adult patients, there are significant gaps regarding the data of adolescents and children with HCV infection. Although several DAAs are effective and safe in adolescents with hepatitis C (8,49), it is unclear whether a shorter 8-week treatment cycle would achieve similar outcomes as the 12-week or even 24-week cycles. To this end, we systematically analyzed the studies published so far on the therapeutic efficacy of DAA-containing regimens in children and adolescents with HCV infection. Prior to the regulatory approval of DAAs for pediatric patient, the standard treatment for adolescents and children infected with HCV was 24 weeks of pegIFN and RBV for GT 2 and 3, and 48 weeks for GT 1 and 4 (50)(51)(52)(53)(54)(55)(56)(57)(58). This combination resulted in an SVR of around 52% in patients infected with HCV GT 1 and 4, and 89% in those infected with HCV GT 2 and 3, but was associated with significant side effects (54)(55)(56)58). Compared to IFN-based regimens, DAAs not only are more efficient but also have fewer side effects (10-12, 15-17, 22, 24-26, 28, 29, 31, 34-39). We found that the overall SVR12 rate for the adolescents and children treated with DAAs was 99.4 and 98.9%, respectively, although the frequency of AEs was substantial (34.7 and 51.6%). Nevertheless, SAEs were rare (0.2 and 1.1%) and no adolescent patients discontinued treatment due to the AEs since most were tolerable, such as headaches (22.6%), abdominal pain (21.1%), and fatigue (15.5%). Moreover, children were more likely to experience side effects compared to teenagers (51.6 vs. 34.7%). The most common AE among children was fatigue (28.4%), most likely due to "abnormal drug taste" (24,26). Thus, DAAs are relatively well-tolerated by both children and adolescents.
Apart from efficacy and safety, cost-effectiveness is also an important issue for any drug regimen (59). Kohli et al. weeks of glecaprevir/pibrentasvir (G/P) is equally effective in treatment-naive non-cirrhotic adults (63). We did not detect any significant differences between the various treatment durations   in terms of efficacy in adolescents or children (P b = 0.398, P d = 0.716). Hesham et al. also found that 8 weeks of treatment with the SOF/LDV combination was as effective and safe as the 12-week regimen in adolescent GT4 patients (15). Similar results were reported by Mortada et al. (38). As for the treatment cycle of 24 weeks, most just appeared in RBV-based regimen in children, because SOF+RBV was also a suboptimal regimen for persons with GT 3 infection, especially if they have liver cirrhosis (8). We found that both 8-week and 12/24-week treatment courses were well-tolerated in adolescents (31 vs. 36.1%/41.7%, P = 0.918), whereas the AE rate at 24 weeks was greater than that at 8/12 weeks (98.7 vs. 57.8%/45.1%, P < 0.001) in children with CHC. This can be attributed to RBV intolerance, as well as the fact that a longer treatment duration would also increase the chances of detecting AEs that manifest late. The correlation between treatment duration and AEs needs to be studied further. Given the underdeveloped immune system of children and the limited time for which DAAs have been administered to this group, our findings should be interpreted with caution. In addition, we only evaluated the efficacy of DAAs in terms of SVR12, and some subgroups did not have a corresponding control due to ethical reasons. Secondly, stratified analysis of SVR showed that the heterogeneity within the three treatment cycles was somewhat large, but the inter-group heterogeneity was not statistically significant. Lastly, only the FDA-approved DAAs were analyzed in the review. Therefore, the treatment outcomes of novel DAAs will have to be continuously monitored in children.
In conclusion, DAAs are overall effective and well-tolerated in adolescents and children with chronic hepatitis C. The 8-week treatment course is as effective as 12/24 weeks in both adolescents and children.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
ZF and MY: study design and protocol, searches, title, abstract, full-text screening, data abstraction, statistical analyses, interpretation of the data, and drafting the article. ZG and CW: data verification and statistical analyses. CS and YW: statistical analyses and interpretation of the data. JL and CZ: interpretation of the data. PH, CD, and YZ: study design and protocol, interpretation of the data, and drafting the article. ZF, CD, PH, and MY: manuscript revision and question answer. All authors contributed to the article and approved the submitted version.