What Is Known
- There are ∼5 million children in the world with chronic hepatitis C viremia.
- Present Food and Drug Administration–approved therapy for children with chronic hepatitis C is pegylated interferon with ribavirin.
- Durability of viral response in children treated with non–pegylated interferon and ribavirin is ∼98% at 5 years of follow-up.
What Is New
- Durability of viral response in children with hepatitis C virus treated with pegylated interferon and ribavirin is ∼100% at 4 to 7 years of follow-up.
- Viral response in children treated with pegylated interferon and ribavirin is higher in children with IL28B CC versus those with non-CC.
Hepatitis C virus (HCV) infection is a significant global health burden, with an estimated prevalence of ∼115 million people globally (1.6% of the world's population) (1). A total of 11 million of these individuals are <15 years of age, of whom 5 million are viremic (1). Children in China, Pakistan, Nigeria, Egypt, India, and Russia account for >50% of the total pediatric infections (1). Pediatric HCV infection prevalence varies significantly by region, ranging from 0.05% to 0.36% in the United States and Europe to 1.8% to 5.8% in some developing countries (2). A similar trend is observed in the ratio of the prevalence of HCV in children compared with adults, which varies from ∼1:25 in high-income countries to 1:4 in middle-income countries, and as high as 1:2 in low-income countries (1). Although vertical (mother-to-infant) transmission is the major route of pediatric infection in developed countries, horizontal transmission (eg contaminated needles or blood transfusion products) is the major route in developing countries (2).
The PEDS-C study enrolled 114 children with chronic hepatitis C (CHC) into a clinical trial of pegylated interferon (PegIFN) alfa-2a (Pegasys, Hoffman La Roche, Nutley, NJ) plus ribavirin (RBV, Copegus, Hoffman La Roche) or placebo from December 2004 to May 2006, and the last patient completed the 2-year follow-up in February 2010 (3). The sustained virological response (SVR) rate was 53% (n = 29/55) in children treated with combination therapy and 20% (n = 12/59) in those treated with PegIFN alfa-2a plus placebo (P < 0.001). SVR was maintained in 100% of children who were followed up for 2 years after cessation of therapy. In addition, 28 of 59 patients treated with PegIFN alfa-2a plus placebo were HCV RNA-positive at week 24, deemed nonresponders, and received additional “open-label” compassionate use PegIFN alfa-2a + RBV treatment for a further 48-weeks duration. A total of 11 of these 28 patients (39%) ultimately achieved SVR, which was maintained in all of the patients 2 years after completing treatment.
Longer term durability of response in children treated with PegIFN with or without RBV has not been reported to date. In adults, durability of SVR 5 years after completing PegIFN treatment has been observed to be >99% (4), and cirrhosis appears to be a risk factor for long-term relapse (5). The only published report of long-term follow-up (LTFU) in children is following non–pegylated interferon treatment thrice weekly with RBV, in which the Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI 95–100) (6).
In adults with genotype 1 infection, several independent genome-wide association studies reported single nucleotide polymorphisms near the IL28B (IFN-k) locus to be predictive of treatment response (7,8). Although recently a few pediatric studies have explored the effect of IL28B polymorphism on SVR in children, its role as a predictor of durability of response to treatment is still undetermined (9).
The purpose of the present study was to perform a LTFU, up to 7 years after cessation of therapy, of a group of children previously treated with PegIFN alfa-2a ± RBV in the PEDS-C study, and assess the long-term durability of SVR, long-term safety and tolerability, and the association between IL28B polymorphism and treatment response.
Patients were eligible for inclusion if they completed treatment with PegIFN alfa-2a ± RBV in the PEDS-C study. Patients were excluded if they received PegIFN alfa-2a ± RBV after the initial study period, received other treatment that the investigator judged could affect growth (eg growth hormone therapy), or experienced serious illnesses unrelated to PegIFN treatment requiring >72 hours hospitalization that may have a negative impact on growth.
The institutional review board at each site and the Clinical Trials and Survey Corporation approved the study protocol. Informed consent was obtained from all of the patients, who were subsequently seen at study entry, contacted by telephone 4 and 8 months later, and seen again 1 year after study entry. Clinical and laboratory information collected included HCV RNA (TaqMan-2.0-EDTA-C Assay, LLOD 10 IU/mL), clinical chemistries and thyroid function tests, IL28B polymorphisms (single nucleotide polymorphisms at rs12979860, comparing genotype CC vs CT/TT) (10), and health-related quality-of-life data.
Descriptive statistics were used for all analyses with exploratory analyses performed as appropriate. All statistical tests were 2-sided and used the conventional P < 0.05 level of significance, with χ2 and independent t test being used as appropriate. RNA values were log-transformed to improve interpretability. All of the analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC).
All of the 93 patients who had completed the 2-year follow-up in the original PEDS-C study, from 8 participating sites, were considered for enrollment. A total of 38 were available and willing to participate in the LTFU study. Of the 55 others, 26 were not contactable, 8 had moved from the area, 7 received PegIFN/RBV retreatment, and 14 either refused consent or could not participate for other reasons. The patient disposition in the original PEDS-C study and the present LTFU study is shown in Figure 1.
The LTFU cohort was found to be the representative of the original PEDS-C cohort, both in terms of baseline characteristics (eg HCV genotypes) and treatment received (Table 1). A total of 21 (55%) subjects had received PegIFN alfa-2a + RBV, whereas 17 (45%) received PegIFN alfa-2a + placebo treatment. A total of 10 of the 17 subjects treated with PegIFN alfa-2a + placebo, received additional PegIFN alfa-2a + RBV treatment for 24 to 48 weeks duration, after study week 24 via the “compassionate use” treatment arm.
Durability of SVR
HCV RNA levels remained undetectable in 100% of responders but remained high in all nonresponders during LTFU. Mean alanine aminotransferase levels were significantly lower in responders compared with nonresponders at all follow-up time points. For example, at LTFU visit 1, mean ALT levels in responders were normal at 23 U/L (95% CI 19–27), whereas they were elevated in nonresponders at 53 U/L (95% CI 32–75) (P < 0.05).
IL28B and SVR
IL28B CC genotype was associated with higher rate of SVR, compared with CT/TT genotype (67% vs 30% respectively, P = 0.028) (Fig. 2).
There were no patient deaths, and only 1 serious adverse event (hospitalization for depression) was reported. This serious adverse event occurred 6.5 years after treatment and was deemed unrelated to the study treatment. There were no clinically significant changes in any laboratory or vital sign parameters with the exception of the HCV RNA and ALT values discussed above.
Long-term growth outcomes have been previously reported (11), and overall no long-term effects on height were observed. The results of health-related quality-of-life questionnaires will be reported separately.
The major finding of the present study is that SVR following PegIFN alfa-2a ± RBV therapy in children with CHC is durable in 100% of the patients for 4.4 to 7.7 years after treatment cessation. IL28B CC genotype was also observed to be associated with a greater chance of an SVR (P = 0.028), which is consistent with data from adult and recent pediatric studies with CHC. Furthermore, PegIFN alfa-2a also shows an excellent long-term safety profile in the treatment of children with HCV, including the absence of long-term effects on growth (11).
The significance of the above finding is that PegIFN alfa-2a is currently widely available to the considerable global population of children and adolescents with HCV. Indeed, it has been estimated that ∼50,000 HCV-infected infants are born every year (12), a fact which is especially sobering given that at present there is no known way to prevent maternal-fetal transmission.
Although direct acting antiviral agents currently hold great promise for highly effective interferon-free treatment regimens (13), none have yet been approved for use in children, and there could be challenges to widespread availability to children, particularly in low-income countries where the prevalence and burden of HCV infection is the greatest.
The main limitation of the present study is the relatively small number of patients who participated in the LTFU. This is not surprising given that the average age of enrollees in the original PEDS-C study was 11 years, and the LTFU lasted up to 7.7 years after cessation of therapy. This meant that many patients had moved away from home for higher education or employment, and were simply not available for participation in the LTFU study; however, the fact that the baseline and treatment characteristics of the LTFU cohort did not differ from the PEDS-C cohort indicates that the smaller LTFU cohort is the representative of the original larger cohort. So, it is unlikely that the 100% long-term durability rates observed in the LTFU cohort would significantly differ if the entire PEDS-C cohort participated in the LTFU.
Overall, the PEDS-C LTFU data indicate that children who achieve SVR during the treatment with PegIFN alfa-2a, with or without RBV, have a high likelihood of long-term maintenance of that response. Given the ∼5 million HCV-infected children in the world, the present lack of approved direct-acting antiviral interferon-free regimes in the pediatric population, and the potential limited access to interferon-free regimens in the developing countries where HCV prevalence is the highest, it is reassuring to confirm that SVR achieved in children with CHC with the present standard of care will be maintained for many years.
The authors thank external patient safety committee members Ann Scheimann and Dolores Njoku for the review of the annual laboratory abnormalities; research coordinators Timothy Crisci, Shannon Fleck, Marcia B. Hodik, Kim Kafka, Ann Klipsch, Oyinkansola Kusemiju, Roshan Raza, and Melissa Young; and Irene Cheng of the Clinical Trials and Survey Corporation. The authors also thank Hoffman La Roche for their input into study design and data analysis, the PEDS-C network, and our patients and families.
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