It is now clear that HCV has a number of unique metabolic effects on the host that, in turn, render the infected person more vulnerable to adverse health outcomes. These effects, including hepatic steatosis, insulin resistance, and lipid changes, seem to be additionally aggravated by the presence of overweight and obesity. Compounding matters, there is evidence that steatosis and insulin resistance also adversely affect the success of antiviral therapy for HCV (24
). The proposed mechanisms linking obesity to diminished response to HCV therapy include: decreased interferon bioavailability, altered cytokine function, and insulin resistance (8
). However, definitive conclusions about the independent contribution of increased BMI to HCV progression and response to therapy have not been reached.
In this investigation, we selected a pediatric cohort to ensure the use of weight-based dosing in antiviral regimens and to minimize comorbidities and potential confounders. Two groups with unique inclusion and exclusion criteria were selected in order to address the primary questions of interest: (1
) what is the role of overweight in progression of HCV liver disease? and (2
) what is the effect of overweight on response to antiviral therapy?
In STUDY 1, we found that overweight is associated with the development of steatosis in HCV infection. This finding could not be accounted for by varying age or infection duration among our subjects. Although the role of race or ethnicity could not be formally evaluated in our study, having a relatively uniform cohort precludes possible confounding based on racial differences. Though statistical significance was not demonstrated, there was a trend towards more extensive fibrosis among those who were overweight. A retrospective investigation by Giannattasio et al. evaluated 64 children from Naples, Italy, undergoing liver biopsy (30
). Their study population carried mostly HCV genotype 1, and the distribution of steatosis was similar to that in our investigation, namely, 25% of children with either mild or moderate steatosis and 75% without steatosis. Giannattasio et al. did not find an association between BMI and steatosis in their cohort. The reason for the discrepancy in this regard with our results is unclear but might be explained by geographic and environmental differences. Interestingly, Giannattasio found an association between steatosis and greater fibrosis.
A more recent prospective multicenter trial, the PEDS-C Trial, demonstrated results more consistent with our findings. This trial investigated a total of 121 children from 11 United States Centers (31
). They found that 32% of their subjects had minimal and 9% had mild steatosis, while severe steatosis was not observed. There was a statistically significant correlation between presence of steatosis and overweight in accordance with our data. Similarly, they did not find a statistically significant correlation between fibrosis and BMI. However, when categorizing subjects as lean vs. overweight they found significantly greater fibrosis in overweight children. In our investigation we observed a trend towards greater fibrosis in overweight children but this did not achieve statistical significance. We believe that a stronger association between increasing BMI and fibrosis in our cohort would likely have been manifest with longer-term followup. In addition, it is also possible that newer methods that assess fibrosis in a more comprehensive manner, such as elastography, could yield more informative results. Nevertheless, in light of the evidence supporting a positive correlation between steatosis and fibrosis (10
), it seems clear that overweight poses a risk of progression to steatosis and possibly future fibrosis in youth chronically infected with HCV.
In STUDY 2, we noted a univariate association between overweight and higher BMI percentile with non-response to HCV therapy. A statistically higher percentage of therapy nonresponders were overweight when compared to responders, and nonresponders had higher baseline mean BMI percentiles for equivalent age and gender. When evaluating additional variables, we observed that use of ribavirin was associated with improved SVR, while genotype 1 or 4 were associated with diminished SVR. Increasing BMI Z score during the course of therapy was also associated with diminished response to therapy, although this was not statistically significant. More importantly, a higher baseline BMI Z score was independently associated with diminished response in multivariate analysis. In other words, the association noted in univariate analysis became stronger when accounting for important potential confounders. Based on the multivariate model one unit increase in baseline BMI Z score was associated with a 12% decrease in the probability of SVR. These results could not be explained by differences in infection duration, genotype, treatment used or any of the other variables analyzed. It is noteworthy that in both STUDY 1 and STUDY 2, BMI proved to be stable as there was a strong and statistically significant correlation in BMI within one year period. Stability of BMI for longer periods of time has also been previously demonstrated in both children and adults (33
Although weight-based dosing was used in this study, the upper limits set on dosages are a potential limitation. However, review of BMI levels demonstrated that there were no morbidly obese patients in our cohort and there were no statistically significant differences in raw BMI values between the two comparison groups. Thus, it is unlikely that our findings could be explained by relative underdosing of heavier patients. Another potential limitation of this investigation is its retrospective nature. As a consequence, more than one treatment modality was included in this investigation. However, there was no selection bias as treatment was not chosen based on subjects' BMI values. In addition, careful evaluation of treatment modality revealed that this was not a confounder in the association between BMI and response to therapy. Use of ribavirin was associated with improved response, but subjects who received ribavirin had higher mean BMI z scores and still had lower percentages of eradication of the virus which does not support confounding by treatment. Through multivariate analyses, the independent effects of treatment and BMI were simultaneously evaluated in the final model and reported in . Because of the retrospective nature of this investigation there were no sample size calculations obtained a priori. Nevertheless, it is unlikely that a larger sample size would have significantly altered our results. Post-hoc calculations of frequency of overweight among patients with significant fibrosis suggest that approximately 560 subjects (280 subjects in the “high fibrosis” and 280 subjects in the “low fibrosis” groups) would be needed to statistically detect a 12% difference (47% versus 35%) at a power of 80%, based on a two tailed test with an alpha level of .05. The clinical significance of this difference in fibrosis is unclear, but it is possible that different methods of assessing fibrosis would be more appropriate and might lead to more meaningful results. Based on our results, controlling overweight prior to therapy should improve the probability of eradication of HCV infection. Despite the apparent protective effect of even very low BMI's from our results, at this point we would not recommend weight reduction below a BMI of 50th
percentile for age and gender. Prospective studies may provide a more accurate assessment of the actual effect of change in BMI prior to initiation of treatment on response to therapy through the evaluation of individual fluctuations in BMI. We postulate that such prospective studies may reveal stronger effects than those noted here given the evidence available with regards to the effects of even moderate weight loss on abnormal liver enzymes or metabolic risk factors and other conditions (35
In summary, our study suggests that overweight adversely affects the progression of chronic HCV liver disease by way of steatosis and demonstrates an association between overweight prior to therapy with diminished response to antiviral therapy using weight-based dosing in a cohort with minimal confounding variables. We believe our results are generalizable to the HCV-infected population at large, including children and adults. Prospective studies to evaluate the effect of weight control on response to HCV therapy will be critical in an attempt to halt the progression and improve the odds of sustained clearance of an otherwise progressive disease of young people.