Effectiveness and Safety of Direct-acting Antivirals for Treatment of Adolescents With HCV/HIV Coinfection: Real-world Data From Europe

We evaluated the effectiveness and safety of direct-acting antivirals in adolescents with hepatitis C (HCV)/HIV coinfection using pooled individual patient-level data from 5 European cohorts. Of 122 participants in follow-up from November 2013 to August 2021, 19 were treated <18 years of age; of 15 with HCV RNA available at/after 12 weeks post-treatment, all had sustained virologic response with acceptable safety. This evidence addresses an important gap in knowledge of treatment outcomes in adolescents with HCV/HIV coinfection in real-life settings.

2013 (date of first approval of DAAs in adults by the EMA 8 ) were included in the study.This date was taken as a starting date to capture any early off-label use in the pediatric population.The latest date for the data cutoff varied across cohorts, from December 2020 to August 2021.
Participants within the selected cohorts who had positive HCV antibody at ≥18 months of age or HCV RNA at ≥6 months of age and were in follow-up during the defined period were included.Those <18 years of age and in follow-up after the DAA approval date were included in the analysis of DAA uptake.DAA treatment effectiveness was defined as the absence of quantifiable HCV RNA in serum after 12 weeks post-DAA treatment completion (SVR12).0][11] Pretreatment values were the closest measurements available to DAA start date (from 6 months before, up to and including treatment start date).ASTto-platelet ratio index (APRI) and Fibrosis-4 score (FIB-4) at preand during treatment were calculated; an APRI score of ≥1.5 and a FIB-4 score of ≥3.25 were considered an indicator of significant and advanced fibrosis, respectively. 12Median [interquartile range (IQR)] of all markers are described, along with changes in division of AIDS grade or FIB-4 and APRI category during treatment.Post-treatment laboratory measurements were not available due to the short duration of follow-up post-treatment in data for analysis.Data analysis was conducted using Stata (17.0, StataCorp LLC, College Station, TX).

RESULTS
Data from 5 cohorts in Spain, Poland and the Russian Federation were included in this analysis.The Spanish cohort is a multicenter cohort while the Polish cohort and the 3 cohorts in Russia are all single-center cohorts based in large pediatric infections referral centers.
Of 2414 children and adolescents ever in pediatric HIV care in the 5 cohorts, 146 (6%) had documented HCV diagnosis with positive HCV antibody or HCV RNA results at a median age of 6.3 [IQR 2.3, 9.0] years.Of these, 4 (3%) died and 20 (14%) exited the cohorts prior to the start follow-up date (Fig. 1).Of the 4 deaths, 1 was due to liver failure related to HCV at age 16.5 years; 2 deaths were unrelated to HCV and 1 had an unknown cause.
Of the 146 participants, 122 (84%) remained in follow-up after the start follow-up date and 90/122 (74%) were viremic.Nineteen participants had initiated DAA treatment <18 years old and 21 at age ≥18 years.One participant died without starting DAAs (not HCV related).

Changes in Laboratory Biomarkers and Fibrosis Assessments
Pre-DAA treatment ALT and AST measurements were available for 17 participants, of whom 7 (41%) and 4 (24%) had raised ALT or AST, respectively, all at grade ≤2 (Table 1).All normalized during treatment, except for 1 participant with no measurements available after treatment start.One participant with normal AST pretreatment had grade 1 raised AST during treatment.APRI and FIB-4 scores were available for 15 participants pretreatment (Table 1); none had scores indicating significant or advanced fibrosis either pre-or during treatment.
One participant was reported to have liver cirrhosis pretreatment, confirmed on liver biopsy, with transient elastography (TE, FibroScan) 14 kilopascals (kPa) at DAA start (age 16.8 years) and normal APRI and FIB-4 scores.This participant received SOF/ LDV and achieved SVR12.At approximately 18 months after completion of DAA treatment, TE result increased to 25.9 kPa, although no clinical or laboratory liver disease decompensation was observed and HCV RNA remained undetectable.

DISCUSSION
2][3] This is one of the first studies reporting the effectiveness and safety of DAAs in adolescents with HCV coinfection.Despite the importance of treatment in this population living with coinfection, it is possible that a significant number of children and adolescents with HCV/HIV remained untreated for 7 or more years after DAAs were first approved in adults in Europe, reflecting the time-lag in regulatory approval and access to new treatments in the pediatric population.Among those treated, all were adolescents.All 15 participants with available HCV RNA results at/after 12 weeks post-treatment completion achieved SVR12.Due to 4 missing SVR12 results, the conservative estimation of effectiveness is at least 79% in this cohort.There were no reports of serious clinical or laboratory adverse events or adverse events leading to treatment change or discontinuation.Our conservative SVR12 results are lower than previously reported due to missing data in 4 participants, but among those with data, the DAA safety was consistent with casestudies reporting excellent safety in adolescents 6,7 and adults with HCV/HIV coinfection. 13,14The favorable treatment outcomes support WHO and European recommendations to treat all children and adolescents with chronic HCV 3 years old and above, including those with normal liver function tests and no evidence of liver fibrosis. 5,15Further data on DAA treatment outcomes in younger children (preadolescence) are needed to confirm the safety and effectiveness. 5,15,16verall, laboratory markers of liver function improved after start of treatment, with ALT and AST normalizing in all participants with raised pretreatment values.No participants were classified as having significant fibrosis using APRI and FIB-4 scores either before or during treatment, however, it is important to note that these measures have not been validated in children.Other limitations of the study include lack of data on DAA dosage and we did not assess change in HIV outcomes post-DAA treatment.
Importantly, 1 participant had cirrhosis at age 16 years, confirmed on liver biopsy.For this patient, elevated transaminases, ART and other factors could have caused an increase in the