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High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C
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Hepatology; September 2003, Volume 38, Number 3
Bressler, Guindi, Tomlinson, Heathcote. Departments of 1Medicine, 2Pathology, and 3Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.
“….Obese patients as judged by their BMI, independent of genotype and cirrhosis, had approximately an 80% lower chance of a sustained response to therapy compared with normal or overweight patients…”
The aim of this study was to determine if body mass index (BMI) was an independent predictor of response to antiviral treatment in patients with chronic hepatitis C.
A retrospective review was performed of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000. A sustained response was defined as either negative hepatitis C virus (HCV) RNA by polymerase chain reaction and/or normal alanine aminotransferase (ALT) level (only in those treated before availability of HCV RNA testing) 6 months following completion of therapy.
All patients were classified into one of 3 groups according to BMI (normal, <25 kg/m2; overweight, 25-30 kg/m2; obese, >30 kg/m2). A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin. Patients were excluded if predetermined clinical characteristics were unavailable.
Using logistic regression, and after adjusting for the examined variables (age, sex, history of alcohol consumption >50 g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood ratio tests showed significant differences in response to treatment according to BMI group (P = .01), genotype (P < .01), and cirrhosis (P < .01).
Those with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 compared with those with genotype 1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients. Hepatic steatosis was not an independent risk factor for response to antiviral treatment.
In conclusion, obesity, only when defined as a BMI greater than 30 kg/m2, is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment.
Author Discussion
Our data suggest that obesity, only as defined by a BMI greater than 30 kg/m2, is a risk factor for nonresponse to antiviral therapy independent of genotype and the presence of cirrhosis on pretreatment liver biopsy in patients with chronic hepatitis C. Obese patients as judged by their BMI, independent of genotype and cirrhosis, had approximately an 80% lower chance of a sustained response to therapy compared with normal or overweight patients. Cirrhosis or HCV genotype 1 were found to be other independent negative predictors of response to antiviral therapy. These data have provided information that can be used by physicians and patients alike to establish the chance of a sustained response depending on each unique clinical situation. Our study did not have a sample size large enough to analyze the effect of treatment type on response.
Previous studies have used weight as a marker to define obesity. We believe that a more accurate way to separate individuals, according to their body habitus, is by a measure albeit indirect of total body fat content. The BMI, which describes relative weight for height, correlates with total body fat content, whereas weight on its own may not.
The mechanism whereby obesity may affect the antiviral response to treatment is not completely understood. BMI has been shown to correlate with the degree of steatosis seen in hepatitis C, and our study confirms this association. Steatosis leads to an increase in lipid deposits within cells25 that may cause a functional disturbance by decreasing the contact area between the drugs and the hepatocytes containing the virus, thus causing a reduction in antiviral drug efficacy. Furthermore, the degree of steatosis has been shown to correlate with the severity of fibrosis. Clouston et al. showed that this relationship between steatosis and fibrosis in patients with chronic hepatitis C was significantly associated with steatohepatitis-like perisinusoidal fibrosis in acinar zone 3. Our study did not show an association between the presence of greater than 5% steatosis with sinusoidal fibrosis; however, it did show that BMI and fibrosis were risk factors for nonresponse but independent of each other. It has also been shown that HCV genotype 3a is associated with steatosis independent of body weight. However, individuals infected with genotype 3a, although they may have hepatic steatosis, have an excellent response to antiviral therapy. In those with genotype 3a, hepatic steatosis disappears with loss of viremia. The response of patients with genotype 3a to antiviral treatment indicates that it cannot be hepatic steatosis alone that decreases the antiviral response. Our study showed that, even though a BMI greater than 30 kg/m2 predicts the presence of hepatic steatosis, it is only the BMI that remains an independent risk factor for a poor sustained response to antiviral treatment. Furthermore, the presence of hepatic steatosis does not influence a patient's response to antiviral therapy when their BMI is taken into account.
At the time these patients received their antiviral therapy, the effect of weight on response was not appreciated, but patients had to have received 80% of the recommended doses of IFN and ribavirin (except for 6 patients who received 40-kd pegylated IFN monotherapy at a dose that was subsequently deemed too small by the manufacturer) to be included in the study.
One study has shown that the pharmacologic effect of IFN on the induction of 2,5´-oligoadenylatesynthetase, an enzyme induced by IFN, is reduced in obese patients following an injection of standard IFN.19 Response to IFN in obese individuals could cause a reduction in the initial absorption of drug given subcutaneously because of an increase in subcutaneous fat. This may be particularly relevant if the injection of IFN is abdominal because abdominal fat mass measured by waist circumference is associated with hepatic steatosis, thus compounding nonresponsiveness.15 Therefore, there could be multiple mechanisms contributing to the nonresponsiveness of individuals with large waist circumferences.
The structural property of some pegylated IFNs is such that its size precludes rapid uptake into the vascular system. Large proteins (>15 kd) injected subcutaneously are primarily taken up by the lymphatic system. Furthermore, examining the lymphatic transfer of a series of compounds with increasing molecular weights has led to the conclusion that there is a direct correlation between larger-molecular-weight molecules and the greater extent of lymphatic absorption and reduced volume of distribution. Therefore, standard IFN is absorbed through blood capillaries and the lymphatic circulation; however, because of the size of some pegylated IFN, they may be predominately taken up by the lymphatics. Obese people are known to have poor lymphatic circulation, and this could potentially lead to lower serum levels of pegylated IFN, thus diminishing the likelihood of a successful antiviral response.
Our data suggest that BMI but not body weight should be considered when advising an individual with chronic hepatitis C of the likelihood of a sustained viral response following a course of antiviral treatment. This study does not address the issue if weight-based dosing of standard and pegylated IFN would compensate for the lower response rate in patients with a BMI greater than 30 kg/m2. Prospective studies are needed to investigate the response rate in obese patients using higher doses of pegylated IFN. Furthermore, if the BMI specifically reduces the antiviral response, weight reduction may enhance antiviral responsiveness in obese patients with chronic hepatitis C.
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