Discussion
In light of the data of this meta-analysis which compared SVR among children with CHC treated by different therapeutic regimens, the combined therapies of PegIFNα or IFNα, plus RV showed significantly higher SVR compared with their respective monotherapies with crude and weighted estimates, irrespective of the HCV genotype. In addition, PegIFNα + RV was significantly superior to IFNα + RV for SVR among cases with G1,2&3 through the weighted estimate. Evidently, CHC cases of G4 treated with PegIFNα + RV showed significantly lower SVR compared to those with G1,2&3 that had been treated with the same regimen. Calculating the SVR according to the genotype in the current analysis was conducted to adjust for a potential bias arising from the significant differences in the genotype distribution between the groups treated with different regimens. The HCV genotype was considered a significant predictor of SVR among adult, and children populations.
This outcome was not in disagreement with our previous meta-analysis report where the crude estimate alone was used without comparison of SVR according to the HCV genotype; albeit the limited number of trials which had been included. Similarly, a subsequent systematic review addressing the issue, did not incorporate a statistical analysis to weigh the differences in outcome and was thus somewhat descriptive. The other systematic review despite using the weighted estimate to assess SVR among children treated with PegIFNα + RV with different HCV genotypes, did not compare the outcome among other regimens, and coalesced the results in G1&4 in one group.
Notably, the crude estimate failed to detect significant SVR differences between some regimens in the current analysis. The weighted estimate calculates the outcome adjusted by a factor (sample size) that reflects inherent difference of each study.
Nevertheless, the significant higher SVR of PegIFNα + RV compared to IFNα + RV among cases with G1,2&3 is in accordance with the outcome of adult randomised, controlled trials. In the absence of such controlled trials to compare SVR for different therapies among children with CHC, and according to our weighted estimate, an evidence-based data approach for the superiority of PegIFNα + RV to IFNα + RV could be applied.
The significantly higher SVR among cases treated with the combined therapies, despite the significantly higher comorbid diseases, compared with their monotherapies, points to potential irrelevant role of comorbid diseases upon SVR.
The wider range of SVR reports among CHC children with G4 (25–75%) in the current analysis differs from the range reported in adults' (50–77%) treated with the same regimen. Such observation may reflect different subtypes in the wide geographical areas or nonadherence to the oral RV taken at home by the children (as PegIFNα was injected at hospitals in some communities), particularly with the lack of proper health education for their parents.
Similarly, the significant higher breakthrough among those treated with IFNα monotherapy compared with other regimens might be explained by nonadherence to the alternate-day IFNα regimen. Nevertheless, adherence to therapy is considered a crucial factor that might alter SVR among patients with CHC.
The nonsignificant rate of relapse between the four regimens in the current analysis is in disagreement with adult studies, where the relapse rate was significantly higher among the groups treated with PegIFNα + RV compared to those treated with IFNα + RV. However, both adult studies do not offer comments and or explanations.
Many trials have recruited children for CHC therapy by the age of 3 years or even less. Enrolment for therapy after at least 3 years of HCV infection has been recommended for children as spontaneous viral clearance rarely evolves after that period. Encourage therapy at 3-year old, where the HCV infection is usually transmitted through the vertical route, has been approved by Food and Drug Administration.
The dose of PegIFNα2b remains debatable. The use of 1 μg/kg/dose, has shown SVR rates of 50% vs. 49–65% among those treated with 1.5 μg/kg/dose. Further research is required for the potential impact of such high dose of PegIFN in the evolution of adverse events which showed higher frequencies in the current analysis compared to the standard IFN.
Notably, in these studies, the mean height percentile remained below the median, up to decrement in height-for-age z score 96 weeks post-therapy, among children treated with PegIFNα + RV whereas median height was retained for children treated with IFNα + RV. However, controlled studies among adults who were treated for CHC did not report significant differences in the overall adverse events between both combined regimens.
Thus, PegIFNα + RV regimen is not optimal therapy for CHC particularly for G1&4 (where SVR was ~50%) among that cohort. The advent of Direct Antiviral agents that target the nonstructural enzymes of HCV involved in viral replication processes has led to the development of IFNα-free regimens with a potential wider applicability than regimens based on IFNα. It will be important to extend these benefits to children, and to ensure that affordable treatment can be provided to areas where the disease is prevalent but mean incomes are low.