High body mass index an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C
Hepatology, September 2003, Volume 38, Number 3

Brian Bressler1, Maha Guindi2, George Tomlinson3, and Jenny Heathcote1 Departments of 1Medicine, 2Pathology, and 3Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

"...Our data suggest that obesity, only as defined by a BMI greater than 30 kg/m2 (not weight), 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…..

"...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…."

ABSTRACT

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 (fatty liver) 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.

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 cells 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.

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. 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. 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.

Editorial in Hepatology: HCV's resistance to treatment is being nurtured by obesity

Arthur J. McCullough, M.D.
Division of Gastroenterology and The Schwartz Center for Metabolism and Nutrition at MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH

Bressler et al. are to be commended for their attempts to estimate body fat mass in 3 different ways: BMI, body surface area, and body weight by quartiles. However, all 3 of these related measurements are potentially inaccurate due to fluid retention in cirrhosis even in the absence of ascites and edema. Therefore, it would have been beneficial if the fluid status and number of patients with cirrhosis had been reported. Another estimate of body fat mass, such as anthropometry, would have supplied additional support for the conclusions based on BMI. In contrast to these limitations, liver biopsy was used to estimate hepatic fat, a parameter that is more reliable and whose pathologic interpretation is accurate and reproducible. However, hepatic fat is not uniformly distributed, and the possibility of sampling error exists.

The second issue is based on the notion of fat distribution being more important than the total body fat mass. Visceral fat has been shown to be a predictor of hepatic steatosis in HCV patients and obesity. Therefore, waist circumferences (not likely to be available in retrospective study) would have been of interest to compare with BMI.

Regardless of these considerations, the two important observations in the current study appear valid. The first is that obesity is an independent factor that diminishes the eradication rate of IFN-based treatment. This confirms previous studies that suggested obesity to be an independent negative predictor of HCV response to treatment. Although the mechanism by which obesity diminishes the efficacy of antiviral treatment in the HCV patients remains to be elucidated, there are at least 3 likely possibilities. (Two were discussed by Bressler). The third possible mechanism is altered immune function associated with obesity, in part mediated by leptin resistance. A rigorous Th-1 response stimulated by antiviral treatment improves HCV clearance with abnormalities in helper T cells and Th1/Th2 ratios being more common in nonresponders to therapies. Leptin is a pleiotropic molecule that regulates T-cell response, polarizing Th cells toward a Th1 phenotype. However, in states of leptin resistance (such as obesity), disordered T-cell function may prevent viral clearance. It should be emphasized that leptin resistance is just one aspect in the mosaic of obesity-induced immunologic abnormalities that may play a role in HCV resistance to treatment.

BACKGROUND

Although the efficacy of antiviral therapy in chronic hepatitis C has improved since standard interferon (IFN) monotherapy was introduced, nonresponse to the current therapies remains common. Several factors have been shown to influence response; these include viral factors (particularly genotype) and host factors, which may be genetic (sex, HLA type, cytokine polymorphisms),1-3 and others such as age, presence of cirrhosis, and race.

In patients with chronic hepatitis C, the degree of hepatic steatosis and fibrosis has been shown by some to correlate with body mass index (BMI), whereas others report that this is not so. Steatosis may be an important cofactor in both accelerating fibrosis and increasing liver necroinflammatory activity in chronic hepatitis C.

Studies show that severe fibrosis or cirrhosis seen on liver biopsy is associated with a reduced rate of sustained viral response when treatment with either IFN-2b and ribavirin or pegylated 40-kd IFN-2a monotherapy. Obesity, a modifiable risk factor, may have a deleterious effect on treatment response to both pegylated and standard IFN monotherapy. Pharmacodynamic studies indicate that obesity may be associated with a weaker biologic response to standard, exogenous IFN-2b. Alternatively, the greater likelihood of more severe liver disease in obese individuals may be the factor influencing response to antiviral therapy.

The aim of this study was to identify whether obesity defined according to BMI is an independent risk factor for impaired response to antiviral therapy in individuals chronically infected with hepatitis C.

A retrospective review of all patients with chronic hepatitis C at a single center given antiviral therapy from 1989 to 2000 was conducted.

All patients were classified into one of 3 BMI groupings (normal, <25 kg/m2, overweight, 25-30 kg/m2; obese, >30 kg/m2). Patient weight alone, categorized in 3 ways, was also used as a variable to determine the use of this parameter to predict response (bottom one fourth, middle one half, and top one fourth of weights as 3 categories; weight as a continuous predictor; and 2 groups with weight <85 kg compared with >85 kg). Patients were also divided into groups according to their body surface area. Data on patients were collected for sex, age at initiation of treatment, previous ethanol consumption (differentiated as >50 g/d or <50 g/d), hepatitis C virus (HCV) genotype, and evidence of cirrhosis on pretreatment biopsy.

Histologic evaluation

A single pathologist reviewed biopsy specimens with 2 hematoxylin-eosin-stained sections for necroinflammatory grading and 2 Masson trichrome-stained sections for assessment of fibrosis. The histologic variables evaluated were as follows. (1) Large-droplet steatosis was evaluated by 2 methods. The first method was a direct estimate of the percentage of hepatocytes containing large-droplet fat. The second method used the Brunt grading system for steatosis in which steatosis is graded 0 to 3 based on percentage of hepatocytes involved (0, none involved; 1, up to 33%; 2, up to 66%; 3, more than 66%).

RESULTS

A total of 253 patients were treated with either IFN monotherapy (either standard or pegylated) or IFN-2b in combination with ribavirin. Combination treatment was given to 101 (40%) of the patients. Patients were excluded if there were missing data in any of the predetermined variables (except for those treated before availability of genotype testing, who were classified as genotype unknown); thus, 174 patients fulfilled study criteria. Of the 174 patients, 48 received combination standard IFN-2b and ribavirin, 96 received standard IFN-2b monotherapy, and 30 patients received pegylated IFN-2a monotherapy (24 at a weekly dose of 180 µg, one at a weekly dose of 135 µg, and 5 at a weekly dose of 90 µg). Sustained response was achieved by 73 patients (42%); 43 patient responses were confirmed sustained virologic responses. Thirty percent of the 174 patients were female, the mean age of the patients was 44.9 ± 8.6 years, 93 of 174 (53.4%) were genotype 1 (in those in whom genotype was tested), 25 (14.4%) had a history of ethanol consumption greater than 50 g/d, and 42 (24%) had cirrhosis on pretreatment biopsy. Seventy patients (40.2%) had a normal BMI (<25 kg/m2), 69 patients (39.7%) were overweight (25-30 kg/m2), and 35 patients (20.1%) were obese (>30 kg/m2). Mean weight of patients was 78 kg.

In a logistic regression model that included sex, ethanol consumption, viral genotype, cirrhosis on baseline liver biopsy, patient weight according to the 3 categories mentioned, and BMI group, likelihood ratio tests showed significant differences in response to treatment according to BMI group (P = .01), genotype (P < .01), and cirrhosis (P < .01). In particular, those with genotypes 2 or 3 had an odds ratio (OR) for a sustained response of 11.6 compared with genotype 1, patients with cirrhosis had an OR of 0.15 compared with those without cirrhosis, and obese patients (BMI >30 kg/m2) had an OR of 0.24 compared with normal and overweight patients.

The response to treatment was not predicted by a patient being overweight (BMI, 25-30 kg/m2) (OR, 1.7; 95% CI, 0.68-4.2). The probability of a sustained response based on viral genotype, BMI, and liver histology has been calculated.

Those individuals who were obese, cirrhotic, and infected with genotype 1 had a predicted probability of 0.013 (95% CI, 0.0023-0.069) for a sustained response to therapy. Weight on its own rather than calculated BMI as an indicator of obesity did not predict response. There was no pattern of association between treatment response and weight alone evaluated by 3 methods (bottom one fourth, middle one half, and top one fourth of weights as 3 categories; weight as a continuous predictor; and 2 groups with weight <85 kg compared with >85 kg). When body surface area was used instead of BMI in the logistic regression model, increasing body surface area shows a trend to lower success with antiviral treatment (P = .08). However, when body surface area is added to the logistic regression model, which included BMI, body surface area is not a significant factor. On the other hand, with both BMI and body surface area in the same model, BMI remains a significant factor (P = .04).

Evaluation of cohort with liver histology available for reevaluation

Of the 174 patients who were included in our study, 136 had liver biopsy specimens for reevaluation. From this subgroup of patients, 29 had a BMI greater than 30 kg/m2 and 107 patients had a BMI less than or equal to 30 kg/m2. Of the 29 obese patients, 27 (93%) had a steatosis grade of 1 or more; of the 107 patients who were either overweight or had a BMI less than 25 kg/m2, 67 (63%) had a steatosis grade of 1 or more. The grade of steatosis was statistically greater in the obese group compared with the overweight and normal patients (P < .005). Of the 29 obese patients with BMI of >30 kg/m2, 3 (10%) had steatosis grade 2. The presence of greater than 5% large-droplet steatosis was not significantly associated with sinusoidal fibrosis (P = .16). In a logistic regression model that included those variables that were independent predictors of a poor sustained response to therapy in our original cohort (viral genotype, cirrhosis on baseline liver biopsy, and a BMI >30 kg/m2) and steatosis grade (Brunt grading system), likelihood ratio tests showed a BMI greater than 30 kg/m2 to be a significant predictor of response to treatment (P = .05). Steatosis grade of 1 or more was not a statistically significant predictor of response in this model.