Journal of Clinical Nutrition & Dietetics

Keywords

Weight change; Hepatitis C; Treatment outcomes; Virological response

Abbreviations

CHC: Chronic Hepatitis C; EVR: Early Virological Response; peg-IFN: Pegylated Interferon; RVR: Rapid Virological Response; SVR: Sustained Virological Response; TNF: Tumor Necrosis Factor; HCV: Hepatitis C Virus

Introduction

Obesity has been shown to be an independent negative predictor of CHC treatment response. Obesity defined as body weight above 75 kg [1], body surface area above 2 meters square [2] and BMI >30 kg/m2 [3] were independent predictors of non-response to PEGIFN based CHC therapy. Spontaneous weight loss as well as other markers such as cytopenias during IFN therapy were associated with higher treatment response [4-6] and blunted weight loss and cytopenia were associated with a null response to IFN based CHC therapy [7]. However, it is not clear if induction of weight loss prior to starting CHC therapy can improve HCV treatment response.

The most recent estimates of hepatitis C burden show an increase in seroprevalence over the last 15 years to 2.8%, equating to >185 million infections worldwide [8] Of those infected, 20% to 50% will develop cirrhosis and hepatocellular carcinoma. It has been estimated that approximately 20% of individuals infected with the hepatitis C virus (HCV) are obese and that obesity in these individuals is associated with steatosis and higher rate of progression of ? brosis [9, 10]. The past 18 months have witnessed significant advances in the pharmacotherapy of CHC with improved treatment response; however, PEG-IFN and Ribavirin remain as component of CHC therapy [11]. Better understanding of strategies to improve treatment response may help improve CHC management.

Both rapid and early virological responses (RVR and EVR, respectively) are significantly associated with sustained virological response (SVR) (undetectable HCV RNA at 24 weeks after completion of therapy). Patients without an earlyvirological response to PEG-IFN+Ribavirin have less than a 2 percent chance of achieving an SVR, compared with an SVR rate of 65 percent in patients with an EVR. Those who achieve RVR have a 90 percent chance of achieving SVR [12]. There are some predetermined factors associated with non-response such as patient race, age or HCV viral genotype [13]. On the other hand, potentially modifiable factors include obesity and other metabolic syndrome components, particularly insulin resistance. Several trials highlighted the inverse impact of obesity on outcome of CHC treatment [3, 14]. Suggested mechanisms include prevalence of associated steatosis and fibrosis [15, 16], insulin resistance [17-19], and increased systemic inflammatory responses such as high TNF [20]. It has been suggested that management of insulin resistance such as addition of metformin to HCV therapy may improve response to HCV therapy [21].

Spontaneous weight loss during PEG-IFN and Ribavirin therapy of CHC has been shown to correlate with better treatment response [22]. However, the impact of induced weight management prior to CHC therapy on treatment response of obese subjects remains to be established. In this study we evaluated the impact of weight management program to induce weight loss on virological response among overweight subjects.

Materials Methods

Patients

All Patients with chronic hepatitis C confirmed by HCV-RNA who had been referred to the University of Pittsburgh Medical Center (UPMC) for hepatitis C management and provided informed consent were enrolled. Out of 64 patients referred for HCV genotype 1 management who provided consent to the study, 36 completed at least 1 month of HCV therapy and were included in the analysis. Data were missing in patients due to inability to start CHC therapy (n=11) or refusal to participate with nutrition intervention (n=17). The study was approved by the Institutional Review Board of UPMC. Treatment naïve HCV Genotype 1 infected patients were divided into 2 groups; Lean patients, BMI <25 (n=11) and Overweight, BMI ≥ 25 (n=25). The latter received a one-time 15-minute weight loss instruction and pamphlet and enrolled into weight management program with 6 weekly one-hour nutrition and physical exercise educational sessions immediately after initial evaluation followed by monthly follow up. All patients started CHC therapy 6 weeks after initial evaluation (Figure 1).

Figure 1: Research timeline.

Data analysis included demographics (gender, races, age) HCV genotypes, Interferon types (α 2a and α 2b), rates of viral responses by PCR, age, pre-treatment weight (within 6 weeks prior to HCV treatment). Body weight was measured and BMI calculated at time of first appointment, at start of CHC therapy 6 weeks after the initial appointment and 12 weeks after the start of CHC therapy. Weight change was calculated as the change compared to the weight at initial visit. A cutoff point of 3% weight loss was chosen as an indicator of significant weight loss, consistent with the guidelines recommendation to improve steatosis [23]. Body mass index (BMI) was calculated as weight in kg divided by square meter of the height (kg/m²). Overweight was defined as BMI ≥ 25 for both in men and women.

Treatment duration, pre-treatment HCV RNA, liver fibrosis grade, pre-treatment ALT and AST were also documented. Records for different variables were taken at exact time plus or minus 1 month.

Hepatitis C therapy

Hepatitis C therapy consisted of weekly subcutaneous injections of pegylated IFN-α2a or IFN-α2b and daily oral Ribavirin. RVR was defined as undetectable HCV RNA levels after 4 weeks of therapy. EVR was defined as a greater than 2-log10 decline in serum HCV RNA from the pretreatment baseline or an undetectable serum HCV RNA at treatment week 12. All patients received weight based Ribavirin+Pegasys 150 mcg, 6 weeks after their initial evaluation.

HCV genotyping was performed by sequence analysis of a portion of the 5‘untranslated region of the viral genome using Inno-Lipa HCV2 Line Probe Assay (Innogenetics, Ghent, Belgium). Cobas amplicor HCV test (version 2.0; Roche Diagnostics, Branchbrugh, NJ) was used to detect HCV RNA. Quantitative assessment of HCV RNA was done by in-house quantitative real-time RT-PCR assay, Cobas Amplicor HCV Test (version 2.0; Roche Diagnostics, Branchburg, NJ) was used to detect HCV RNA.

Nutrition and exercise interventions

Overweight and obese patients were offered an interventional program including diet and physical activity education. The interventions were based on The Group Lifestyle BalanceTM (GLB) Program [24]. The GLB is a comprehensive lifestyle behavior change program adapted directly from the successful lifestyle intervention used in the National Institutes of Health Diabetes Prevention Program. Each patient was given a weight loss goal of 3% of current body weight and was given a personal calorie goal as well as target fat grams per day. Diet and physical activity education classes were conducted by a Registered Dietitian. Candidates received up to 6 weekly classes followed by remedial educational sessions monthly for a total of 6 months. Each class lasted 1 hour for all participants. Each patient was provided a pedometer and a dietary logs to keep a record of daily dietary intake and physical activity. The dietitian checked dietary logs, discussed any related issues, reinforced and encouraged compliance to the dietary and exercise recommendations in the follow up sessions. The dietary education included healthy food selection, methods and strategies to decrease calorie and fat intake and methods to help achieve and maintain weight loss. The participants were asked to do 2½ hours of brisk physical activity each week by starting with 10 minutes of physical activity such as walking or cycling then gradually increase the activity duration up to 30 minutes. Exercises were done at home or outdoor.

Statistical analysis

Statistical analysis was carried out using SPSS for Windows (version 17) (SPSS Inc. Chicago, IL). Descriptive statistics are presented as mean ± standard deviation for quantitative variables and as percentages for qualitative variables. Intent to treatment analysis included data of all patients who received at least one dose of hepatitis C therapy. The categorical variables were compared using Fisher exact test as appropriate. Statistical significance was set at p ≤ 0.05 (two-tailed).

Results

36 patients completed at least 1 month of HCV therapy and were included in the analysis. 69% of participants had BMI ≥ 25. Mean initial BMI in Lean and overweight groups were 22.3 ± 2.84 and 30.3 ± 3.55, respectively, (Table 1A). Lean group was significantly younger than overweight group with 63.6% and 20% <50 years old, respectively, p=0.011. 42% were males, 77.8% Caucasians, 21.8% African American (Table 1A). There was no statistical difference in age, sex or race between those who lost ≥ 3% of their body and who didn’t among overweight group (Table 1B).

Table 1A: Baseline demographic and clinical characteristics for lean and overweight subjects.

Table 1B: Baseline demographic and clinical characteristics for overweight subjects with and without 3% weight loss.

The mean weight change at start of (week 0), and at 12 weeks of CHC therapy (week 0) compared to weight at initial appointment are summarized in Table 2. Overweight group lost 0.33 kg ± 5.61 during the 6 weeks prior to CHC therapy compared to a loss of 1.95 kg ± 6.41 for lean subjects. At 12 weeks the mean weight loss for overweight and lean groups were 3.44 ± 4.12 and 1.44 kg ± 3.82, respectively. 18% and 20% of lean and overweight groups lost ≥ 3% of their initial body weight at the start of CHC treatment. At week 12, 60% and 27.3% of overweight and lean groups lost ≥ 3% of their weight (Table 3).

Table 2: Summary of weight changes at different times of CHC therapy (Kg).

Table 3: Percentage of patients who achieved 3% weight loss at different times of CHC treatment.

Effect of weight loss on early virological response

EVR for lean and overweight groups 82% vs. 52%, respectively, p=0.092. EVR was compared between overweight subjects who achieved ≥ 3% weight loss and those who didn’t ≥ 3% weight loss at week 12 of CHC therapy in overweight patients was associated with a higher EVR, 69% vs. 33.3%, p=0.036 (Table 4).

Table 4: Early VirologicalResponse (EVR) rates in overweight subjects with and without 3% weight loss.

Discussion

In our study, overweight and obese subjects with CHC had a 15 minutes discussion about nutrition, provided a weight management procure and invited to enroll into a weight management program for 6 weeks prior to starting CHC therapy. Our data revealed that patients enrolled into weight management program prior to IFN based CHC therapy who achieved 3% weight loss at week 12 of PEG-IFN + Ribavirin therapy had significantly higher EVR compared to those without 3% weight loss. The mechanisms of the impact of obesity and potential beneficial role of weight loss on response to IFN bases CRC therapy have not been clearly defined. Possible mechanisms include the effect on hepatic steatosis [25-30], insulin resistance and altered immune response. Weight management has been shown not only to a decrease in steatosis but also improvement in fibrosis severity [25, 26]. Weight reduction in obese patients has been shown to dramatically improve the liver histology and biochemistry of patients with steatosis and results in reversal of steatosis and a reduction of fibrosis level in the liver [27, 28]. A loss of at least 3-5% of body weight appears necessary to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation [23].

The development of insulin resistance in HCV-infected patients is thought to be due to a combination of both host and virusmediated pathways. Host-related factors typically seen in patients with NAFLD, including overweight/obesity decreased physical activity, older age, and diets high in saturated and trans-fatty acids or fructose, are thought to contribute to insulin resistance. Insulin resistance is a significant component of metabolic syndrome and is significantly associated with obesity. In addition, HCV infection is associated with an idiosyncratic relationship with glucose metabolism with negative affects on the response to IFN-based CHC therapy [29]. Insulin resistance is a significant component of metabolic syndrome and is significantly associated with obesity. Improved virological response to IFN based therapy has been reported when patients received metformin in addition to PEG-IFN and Ribavirin [21].

Conclusion

Overweight and obese subjects with chronic hepatitis C who had a 3% weight loss on weight management program starting prior to initiation of antiviral therapy had higher EVR. Weight management programs including diet and exercise regimen before beginning PEG-IFN + Ribavirin therapy of CHC may improve IFN based CHC treatment response and may provide an important adjunct treatment strategy for overweight patients with chronic hepatitis C.

Statement of Authorship

Hossam Kandil and Hany Elwakeel designed and conceived the study, developed the overall research plan and provided the database essential for research. Sherif Elbehiry wrote the first draft. Hossam Kandil, Sherif Elbehiry, Laura Matarese, Hany Elwakeel, Kareem Kandil and Eslam Ali helped with statistical analysis, interpreted the data and reviewed the manuscript for submission. All authors have read and approved the final manuscript. The data were collected at University of Pittsburgh. Data analysis and manuscript preparation were done at East Carolina University.

Acknowledgement

This study was supported by educational grant funded by the Egyptian ministry of the higher education.

References

1. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, et al. (2002) PegIFN alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347: 975-982.
2. Zeuzem S, Feinman S, Rasenack J, Brunda MJ (2000) PegIFN alfa-2a in patients with chronic hepatitis C. N Engl J Med 343: 1666-1672.
3. Bressler BL, Guindi M, Tomlinson G, Heathcote J (2003) High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 38: 639-644.
4. Chung RT, Poordad FF, Hassanein T, Zhou X, Lentz E (2010) Association of host pharmacodynamic effects with virologic response to pegylated interferon alpha-2a/Ribavirin in chronic hepatitis C. Hepatology 52: 1906-1914.
5. Suwantarat N, Tice AD, Khawcharoenporn T, Chow DC (2010) Weight loss, leucopenia and thrombocytopenia associated with sustained virological response to hepatitis C treatment. Int J Med Sci 7: 36-42.
6. Rodriguez TM, Sulkowski MS, Chung RT, Hamzeh FM, Jensen DM (2010) Factors associated with rapid and early virologic response to peginterferon alfa-2a/Ribavirin treatment in HCV genotype 1 patients representative of the general chronic hepatitis C population. J Viral Hepatitis 17: 139-147.
7. Lindsay K, Morishima C, Wright EC, Dienstag JL,Shiffman ML, et al. (2008) Blunted cytopenias and weight loss: new correlates of virologic null response to re-treatment of chronic hepatitis C. ClinGastroenterolHepatol 6: 234-241.
8. Mohd HK, Groeger J, Flaxman AD, Wiersma ST (2013)Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57: 1333-1342.
9. Hoofnagle JH, Sherker AH (2014) Therapy for Hepatitis C - The Costs of Success. N Engl J Med 370:1552-1553.
10. Strader DB, Wright T, Thomas DL, Seeff LB (2004) AASLD practice guideline: diagnosis, management, and treatment of hepatitis C. Hepatology 39: 1147-1171.
11. Zoulim F, Liang TJ, Gerbes AL, Aghemo A, Deuffic BS, et al. (2015)Hepatitis C virus treatment in the real world: optimising treatment and access to therapies. Gut 64: 1824-1833.
12. Field MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S (2010) Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 55: 69-75.
13. Thompson AJ, Muir AJ, Sulkowski MS (2010) Interlukin-28B polymorphism improves viral kinetic and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 139: 120
14. Fried MW, Jensen DM, Rodriguez TM, Nyberg LM, Di Bisceglie AM (2008) Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology 48: 1033-1043.
15.  Patton H, Patel K, Behling C, Vallee M, Heaton S, et al. (2004) The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol40:484-490.
16.  Harrison SA, Brunt EM, Qazi RA, Oliver DA, Neuschwander TBA, et al. (2005) Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. ClinGastroenterolHepatol 3:604-609.
17. Lecube A, Hernández C, Genescà J, Esteban JI, Jardf B, et al. (2004) High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care 27:1171-1175.
18.  Mason AL, Lau JYN, Hoang N, Qian KP, Alexander GJ (1999) Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 29:328-333.
19.  D'Souza R, Sabin CA, Foster GR (2005) Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol 100:1509-1515.
20.  Gil A, Aguilera MC (2007) Altered signaling and gene expression associated with the immune system and the inflammatory response in obesity. Br J Nutr 1: 121-126.
21.  Yu JW, Li lS, Zhao YH, Kang P, Yan BZ (2012) The effect of metformin on the efficacy of antiviral therapy in patients with genotpe1 chronic hepatitis C and insulin resistance. Intl J Inf Dis 16:436-441.
22. Alwakeel HR, Zaghla HE, Omar NA, Alashinnawy HA, Rewisha EA, et al. (2013) Spontaneous Weight Change during Chronic Hepatitis C Treatment: Association with Virologic Response Rates. Intl J Med Sci 10: 1830-1836.
23. Chalasani N, Younossi Z, Levine JE, Diehl AM, Brunt EM, et al. (2013) The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55: 2008-2023.
24. Kramer MK, McWilliams JR, Chen HY,Siminerio LM (2011) A community-based diabetes prevention program: evaluation of the group lifestyle balance program delivered by diabetes educators. Diabetes Educ 37: 659-668.
25. Hickman IJ, Jonsson JR, PrinsJB,Ash S, Purdie DM, et al. (2004) Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 53:413-419.
26. Walsh MJ, Jonsson JR, Richardson M,Lipka GM,Purdie DM, et al. (2006) Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut 55:529-535.
27. Adinolfi LE,Gambardella M, Andreana A, Tripodi MF, Utili R, et al. (2001) Steatosis Accelerates the Progression of Liver Damage of Chronic Hepatitis C Patients and Correlates With Specific HCV Genotype and Visceral Obesity. Hepatology 33: 1358-1364.
28. Hickman IJ, Clouston AD, Macdonald GA, Purdie DM,Prins JB, et al. (2002) Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 51: 89-94.
29. Arase Y,Suzuki F, Suzuki Y, Akuta N, Kobayashi M, et al. (2009) Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology 49:739-744.