The directly acting antiviral drugs (DAAs) have revolutionized the treatment for chronic hepatitis C virus (HCV) infection with higher cure rates, shorter courses of therapy and higher safety and tolerability than the previous interferon-based standard of care.1–4
Interferon-based therapy was known to be associated with many adverse effects in children as the case in adults. Peculiar to the growing pediatric age groups, there have been multiple reports of negative effects on linear growth, weight gain and other growth indices in children treated with interferon for chronic hepatitis C or B.5–8 However, the effect of treatment with the new class of DAAs on growth indices in pediatric age groups has not been well evaluated.
Here, we aimed to assess the short-term effects of dual sofosbuvir (SOF) daclatasvir (DCV) therapy on linear growth and weight curves of chronic HCV-infected adolescents during treatment till the end of 12 weeks post-treatment follow-up period.
MATERIALS AND METHODS
This study is an extension of our previous cohort study published earlier.9
The study protocol had been reviewed and approved by the Research Ethics Committee of Faculty of Medicine, Alexandria University (IRB00007555) according to the Declaration of Helsinki. All subjects and their parents/guardians signed the informed consents before the start of the study interventions.
Starting from February 21, 2017, adolescent patients presenting, with chronic HCV infection, to 2 outpatient clinics in Alexandria and 2 in Cairo, Egypt, were subjected to full screening for eligibility criteria. The results of the first 30 consecutively included patients who fulfilled the eligibility criteria and received the treatment were presented in the previously published study report.9 Here, we present the results of the total of 40 included patients under the same protocol with focused analysis on growth indices and virologic response as the primary endpoints.
During the screening/baseline visits (week 0) and all other study visits [weeks 2, 4, 12 [end of treatment (EOT)] and 24 (12 weeks after EOT)], all patients were subjected to full physical examination and investigations as described in the previous report.9
The body weight was measured by an electronic digital scale accurate to 0.1 kg, and the standing height was measured by Stadiometer (UK) to the nearest 0.1 cm. Anthropometric measurements were made during visits by a single observer at each study site. The serum HCV RNA level (virus load) was tested using the polymerase chain reaction quantitative measurements by COBAS Amplicor 2.0 (Roche Molecular Diagnostics, Pleasanton, CA; lower limit of detection of 10 IU/mL).
All patients were subjected to dual SOF/daclatasvir treatment (generic products produced by European Egyptian Pharmaceutical Industries, Alexandria, Egypt), with the same protocol as described in the previously published study for 12-week duration.
The primary outcome in this study included the comparison of means of repeated measures of weight-for-age Z scores (ZWTAGE) and height-for-age Z scores (ZHTAGE) from baseline values (first point) through the EOT (second point) till 12 weeks after EOT (third point).
The proportion of patients achieving sustained virologic response 12 (SVR12) defined as serum HCV RNA below lower level of quantification at week 12 after EOT) on intention to treat (ITT) basis.
Treatment-emergent adverse events as reported by patients or observed by investigators during the study visits were reported and analyzed.
We presented our qualitative data as counts, proportions or percentage with the confidence interval using Wilson Score Interval Method. For quantitative data, descriptive statistics are the arithmetic mean, the standard deviation (SD), the median and the 95% confidence interval whenever found appropriate. A repeated measures analysis of variance (ANOVA) design with 1 “within-factor” (ZWTAGE, ZHTAGE or Z score for body mass index for age (ZBMIAGE)) and 1 group with a total of 40 subjects; each subject is measured 3 times. This design achieves 89% power to test the within-factor if a Geisser-Greenhouse Corrected F test is used with a 5% significance level and the actual effect SD is 0.23.
Forty eligible patients were included in this study analysis and all received treatment with SOF/DCV. During the whole period of the study, only 1 patient was lost to follow-up after achieving the EOT response at 12-week visit.
The demographic and some baseline characteristics are presented in Table, Supplemental Digital Content 1, http://links.lww.com/INF/D332.
By the end of week 4 as well as week 12 of treatment, all patients 40/40 [100%; 95% confidence interval (CI): 91.2%–100%] achieved viral negativity by polymerase chain reaction. The ITT SVR12 rate was 39/40 (97.5%; 95% CI: 87.12%–99.56%). The only patient who did not achieve SVR12 was lost to follow-up after showing viral negativity at the EOT visit.
At baseline, the mean (±SD) weight was 50.75 kg (±12.64 kg), and the mean ZWTAGE was 0.49 (±0.61). After 12 weeks (at the EOT), though the mean weight did slightly increase to 51.77 kg, the mean ZWTAGE showed a slight reduction to 0.45 (±0.61). At the end of the follow-up period (24 weeks after baseline), the mean ZWTAGE showed a larger increase to 0.55 (±0.55) exceeding the baseline level (Fig. 1). Repeated measures ANOVA adjusted for sex and baseline age in months did not detect the statistical significance of the differences in Z scores weight for age (P = 0.56).
The mean (±SD) height as measured in centimeters at baseline was 153.25 (±11.33) cm, with a mean ZHTAGE of −0.32 (±1.04). After 12 weeks (at EOT point), there was a slight increase in mean height to 154.65 (±10.9), but the mean ZHTAGE showed a marked reduction to −0.48 (±0.89). Whereas at the end of the follow-up period (24 weeks after baseline) the mean ZHTAGE showed a slight increase to −0.36 (±1), it did not reach the baseline level (Fig., Supplemental Digital Content 2, http://links.lww.com/INF/D333). Repeated measures ANOVA adjusted for sex and baseline age in months did not detect the statistical significance of these differences (P = 0.301).
The unstandardized mean body mass index (BMI) as a ratio of weight in kg over the squared height in m2 showed a small steady numerical increase from 21.219 (±3.22) kg/m2 at baseline to 21.347 (±2.93) at week 12 and 21.593 (±2.91) at week 24. This might reflect a relative deceleration effect on height in denominator or unbalanced weight acceleration in numerator (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/D334). However, this small insignificant numerical increase was not revealed as we compared the means of BMI Z scores standardized for baseline age and sex (ZBMIAGE) (P = 0.9999) (Fig., Supplemental Digital Content 4, http://links.lww.com/INF/D335) (P = 0.054).
No fatalities or serious adverse events were reported during the study. Only 15 (37.5%) patients reported 23 nonserious treatment-emergent adverse events throughout the study with causality assessment reports as possible or above. These events included nausea reported by 5 patients (12.5%), abdominal pain reported by 6 (15%), fatigue reported by 5 (12.5%), headache by 4 (10%) and pruritus or skin rash by 3 patients (7.5%). All were mild to moderate (≤grade 2) in severity.
The ITT SVR12 rate was 39/40 (97.5%; 95% CI: 87.12–99.56%). This demonstrates concordant efficacy results to other studies on DAAs treatment for chronic HCV at this age group.9,10
Although the repeated measures ANOVA test (Greenhouse-Geisser test of “within-subject” effect) was not statistically significant for both growth indices (ZWTAGE and ZHTAGE), but the results could suggest a relatively higher deceleration effect on height or unbalanced weight acceleration. This could also be seen from the effect on the unstandardized BMI which showed a small steady increase throughout the study, reflecting a slight but relatively larger deceleration effect on height or unbalanced acceleration of weight.
This might partially explain the observation reported by 27 (67.5%) parents/care givers of the patients that they noticed a relative increase in food intake and appetite of their children shortly after starting treatment. This could at least partially compensate for the relatively more apparent (but statistically not significant) deceleration effect on linear growth during treatment.
Many other studies had addressed the issue of the effect of treatment of chronic HCV infection on growth conducted in the era of interferon-based treatment.
Jonas et al5 had demonstrated significant deceleration effects on weight and height during interferon-based therapy. Thereafter, Z scores rebounded toward baseline levels, but the mean ZHTAGE remained significantly lower than baseline at the end of the 96 weeks post-treatment follow-up period.5
While Haber et al6 had also reported significant decreases in height and weight Z scores during treatment. Only partial recovery of ZHTAGE was observed during 5 years of follow-up in patients treated for 48 weeks.
We acknowledge the uncontrolled, nonblinded study design, the small sample size and the relatively short follow-up duration as the main limitations in our study.
In summary, sofosbuvir/daclatasvir combined therapy could be a safe and effective treatment in adolescent patients 12–17 years of age with chronic HCV genotype 4 infections. Unlike interferon-based therapy, we did not detect significant negative effects on linear growth or weight. Contrarily, a trend to increased appetite and insignificant weight gain was observed, but further larger studies are needed to confirm.
Authors’ contributions: M.Y., M.H.E.-S., and S.H. designed the concept of study. M.Y., M.H.E.-S., M.M.A., A.A.M., A.F.K., A.M.A., N.M.K., E.M.K. and H.R.E.-K. recruited the patients, conducted the study procedures and collected the data. M.Y. interpreted the data and wrote the first draft of the manuscript. All authors reviewed the manuscript and approved the final version to be published.
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