Report to Readers
An epidemic hits home
If you were Meg Heckman's boss or colleague or casual acquaintance, you'd easily imagine her to be the picture of health: She is a runner and a skier. She is careful about what she eats. She has a sunny, can-do attitude and the stamina for long hours of hard work.In the summer of 2008, she told me otherwise: Meg, a longtime Concord Monitor journalist, had lived her entire…
December 9, 2010
What is HCV, anyway?
Hepatitis C, or HCV, is a blood-borne virus that infects between 3 and 4 million Americans and about 200 million people worldwide. It causes liver damage, liver cancer and death. For decades, it was a scientific mystery. During the 1960s and 1970s, researchers identified two viruses that inflame the liver. They named one hepatitis A and the other hepatitis B but were puzzled by…
December 12, 2010
My epidemic (Part 1 of 6)
Infected at birth
Sometime in the chaotic hours after my birth, after an ambulance rushed me from Concord to Hanover, after doctors re-inflated my lungs, arranged my tiny body in an incubator and threaded tubes under my skin, I received a few tablespoons of someone else's red blood cells.For two hours, the transfusion dripped into…December 12, 2010.
Tracking government response
In 1998, a report approved by Congress contained stark warnings about the HCV epidemic, decrying "uneven" disease reporting and surveillance, "uncoordinated" research, and limited education on prevention and treatment."Unless confronted more boldly, more directly, and more loudly," the report continued, "the threat posed by hepatitis C will only…
December 13, 2010.
My epidemic (part 2 of 6)
A journey toward diagnosis
When I was a kid, phlebotomists dreaded me. Show me a needle - or even hint that one might be in my immediate future - and I'd pitch a fit. Or run for the nearest exit. My attitude didn't improve much as I aged, but when the Red Cross set up a blood drive in my high school gym, I talked myself into giving a…
December 13, 2010.
'I'm a hepper, not a leper'
For many people with hepatitis C, the public perception of the disease is as challenging as its symptoms. A 2009 study by the Society of Gastroenterology Nurses and Associates found that 84 percent of HCV patients had experienced stigma related to their infection. Other academic papers recount stories of people who were barred from using their relatives' bathrooms, prohibited from…
December 14, 2010.
My epidemic (part 3 of 6)
Surviving stigma
The extent of my social problem dawned on me while I was astride a Stairmaster, halfway through my daily workout. The gym was crawling with college kids, grunting, flirting, dropping weights, making plans for the weekend. I bobbed along, eavesdropping and flipping through the May 1999 issue of Cosmopolitan.Tips for…
December 14, 2010.
My epidemic (part 4 of 6)
Secret world of support
On more nights than I can count, I've curled up on my couch, balanced my laptop on my thighs and entered a virtual world where everyone knows exactly what it's like to have hepatitis C.There are dozens of online chat rooms, message boards and social networking sites for people with hepatitis C, or HCV, a common…
December 15, 2010.
My epidemic (part 5 of 6)
Life as a guinea pig
On May 2, 2008, I walked into an exam room at Dartmouth-Hitchcock Medical Center, collapsed into a chair and declared that I was going to die. Soon.My right shoulder had been aching for weeks, and with the help of a few medical websites, I'd diagnosed myself with liver cancer. This was not a completely irrational…
December 16, 2010.
Emerging treatments out of reach
For HCV patients with access to good health care, the prospects for curing the virus are about to get a lot better, but the future remains grim for the majority of people infected with the disease.Dozens of U.S. pharmaceutical companies are researching cures for hepatitis C, and drugs expected to be released next year have the potential to cure millions. Those medications may be…
December 17, 2010.
My epidemic (Part 6 of 6)
The heart works fine
On a Friday night almost three years ago, I barreled into the Barley House in downtown Concord, late for a blind date. As I looked around the room for a stranger I'd connected with on Match.com, I thought, "What the hell am I doing here?"That afternoon, in an exam room at Dartmouth-Hitchcock Medical Center,…
December 17, 2010.
My epidemic (postscript)
The brave ones
Despite what many of you have told me recently, I am not brave. Last week, the Monitor published a series of stories I wrote about living with hepatitis C, or HCV, a common but little-known virus that damages the liver and can lead to serious health problems, including cancer. You read about how I was infected through a blood transfusion at birth, about the stigma often associated with the disease and about my unsuccessful attempt last year to cure myself through a clinical trial....
December 20, 2010
Monitor editorial
Get serious about curing hepatitis C
By Monitor staff
Last week Monitor reporter Meg Heckman bravely shared the story of her battle with hepatitis C in an attempt to shine some light on a devastating yet little-known problem. Now it's time for our elected officials to show their own courage and get serious about solving it....
December 21, 2010
Letter
Wonderful series
Bill Glahn, Concord
By For the Monitor
My normal habit each morning is to skim the Monitor, check out comments about the Concord School Board and then read it in detail later. Meg Heckman's series on her life with hepatitis C made that impossible...
December 22, 2010
December 22, 2010
Hepatitis C: Another Protease Revolution
Dec 1, 2010
By: Walter Armstrong
Pharmaceutical Executive
The providential similarities between HIV and the Hepatitis C virus (HCV) have enabled researchers at the level of viral dynamics to apply their crisis-driven know-how about designing drugs to target specific proteins and enzymes on the first retrovirus to that of the second. And as with HIV in the mid-'90s, the launch of a new class of protease inhibitors is set to transform HCV treatment over the next decade, with kinder, gentler oral antiviral cocktails that will increase success rates from 50 percent to 75 percent while halving the current onerous course of treatment. "The pipeline has about 100 molecules designed to hit all these new targets—protease, polymerase, RNA-binding proteins," says Matthias Gotte, a virologist whose lab at McGill University tests old compounds for their prowess at outwitting the replication and resistance of HIV, HCV, and herpes.
Vertex's telaprevir is expected to be the first protease out of the FDA gate early next year, followed by Merck's boceprevir by late 2011. Both drugs boast superior efficacy, and their side effects are modest compared to the standard of care: a 24- to 48-week course of weekly injections of interferon boosted by ribavirin, with its 50 percent cure rate due in part to the severe malaise triggered by the immune stimulator. Telaprevir has not only the front-runner's advantage but a slight edge in efficacy. Analysts anticipate a breathless launch by Vertex and Merck alike, and projections of $2.5 billion in annual sales by 2013 for telaprevir are widely shared.
As second fiddle, boceprevir will require standout post-marketing data to grab a heaping piece of a global HCV market expanding to $8 billion by 2014 as a growing number of the 220 million people infected with the virus access diagnosis and treatment. Still, a physician survey by Datamonitor found that 46 percent expect to prescribe telaprevir (with standard of care) to newly diagnosed patients, compared to 26 percent who will choose boceprevir.
"There is still big room for improvement in this class because both drugs have to be dosed three times a day," says Mansi Shah, a Datamonitor analyst. Nipping at their heels is J&J's Phase II protease, TMC435, poised to become the first once-daily treatment. Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, and Roche all have promising protease in Phase II. Because HCV is quick to develop resistance to this class, the most potent, fastest-clearing molecule is likely to seize first-line status.
But the HCV treatment revolution will be in full swing only when an all-oral combination retires IV interferon for good. To that end, each of these six Big Pharmas are also chasing a first-in-class polymerase inhibitor—last month, Roche took the lead by licensing Pharmasset's midstage polymerase, RG7128—and are already testing protease/polymerase dual therapies in Phase II. But the polymerase class poses its own drug-design challenges: Although it is almost free of resistance, one after another targeted molecule has been doomed by high toxicities.
After preliminary data was recently released by BMS at the annual liver-disease conference, Gilead and Vertex stirred worries that a protease/polymerase duo alone lacks sufficient potency for sustained viral control, suggesting that the addition of ribavirin for a triple-drug viral punch will be the gold standard until a third viral protein is pierced or an inhaled—and much milder interferon—comes along. Still, the progress in HCV will bring the pharmaceutical industry glowing global headlines in 2011. Right now thousands of patients with chronic infection and failing livers are literally counting the days until their doctors can write their first scrip for these likely lifesaving drugs.
Source
By: Walter Armstrong
Pharmaceutical Executive
The providential similarities between HIV and the Hepatitis C virus (HCV) have enabled researchers at the level of viral dynamics to apply their crisis-driven know-how about designing drugs to target specific proteins and enzymes on the first retrovirus to that of the second. And as with HIV in the mid-'90s, the launch of a new class of protease inhibitors is set to transform HCV treatment over the next decade, with kinder, gentler oral antiviral cocktails that will increase success rates from 50 percent to 75 percent while halving the current onerous course of treatment. "The pipeline has about 100 molecules designed to hit all these new targets—protease, polymerase, RNA-binding proteins," says Matthias Gotte, a virologist whose lab at McGill University tests old compounds for their prowess at outwitting the replication and resistance of HIV, HCV, and herpes.
Vertex's telaprevir is expected to be the first protease out of the FDA gate early next year, followed by Merck's boceprevir by late 2011. Both drugs boast superior efficacy, and their side effects are modest compared to the standard of care: a 24- to 48-week course of weekly injections of interferon boosted by ribavirin, with its 50 percent cure rate due in part to the severe malaise triggered by the immune stimulator. Telaprevir has not only the front-runner's advantage but a slight edge in efficacy. Analysts anticipate a breathless launch by Vertex and Merck alike, and projections of $2.5 billion in annual sales by 2013 for telaprevir are widely shared.
As second fiddle, boceprevir will require standout post-marketing data to grab a heaping piece of a global HCV market expanding to $8 billion by 2014 as a growing number of the 220 million people infected with the virus access diagnosis and treatment. Still, a physician survey by Datamonitor found that 46 percent expect to prescribe telaprevir (with standard of care) to newly diagnosed patients, compared to 26 percent who will choose boceprevir.
"There is still big room for improvement in this class because both drugs have to be dosed three times a day," says Mansi Shah, a Datamonitor analyst. Nipping at their heels is J&J's Phase II protease, TMC435, poised to become the first once-daily treatment. Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, and Roche all have promising protease in Phase II. Because HCV is quick to develop resistance to this class, the most potent, fastest-clearing molecule is likely to seize first-line status.
But the HCV treatment revolution will be in full swing only when an all-oral combination retires IV interferon for good. To that end, each of these six Big Pharmas are also chasing a first-in-class polymerase inhibitor—last month, Roche took the lead by licensing Pharmasset's midstage polymerase, RG7128—and are already testing protease/polymerase dual therapies in Phase II. But the polymerase class poses its own drug-design challenges: Although it is almost free of resistance, one after another targeted molecule has been doomed by high toxicities.
After preliminary data was recently released by BMS at the annual liver-disease conference, Gilead and Vertex stirred worries that a protease/polymerase duo alone lacks sufficient potency for sustained viral control, suggesting that the addition of ribavirin for a triple-drug viral punch will be the gold standard until a third viral protein is pierced or an inhaled—and much milder interferon—comes along. Still, the progress in HCV will bring the pharmaceutical industry glowing global headlines in 2011. Right now thousands of patients with chronic infection and failing livers are literally counting the days until their doctors can write their first scrip for these likely lifesaving drugs.
Source
Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial
Alimentary Pharmacology & Therapeutics
Volume 33, Issue 1, pages 127–137, January 2011
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Aliment Pharmacol Ther 2011; 33: 127–137
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Introduction
An estimated 130–170 million individuals are chronically infected with hepatitis C virus worldwide.1 Pegylated interferon and ribavirin treatment results in an approximate sustained virological response rate of 55%.2, 3 However, individuals who fail to respond or who are unable to tolerate treatment have few additional options. As such, many patients have turned to complementary and alternative medications (CAM) instead of, or in addition to, standard therapy.4, 5
An extract of the milk thistle plant, silymarin (Silybum marianum), has been used to treat chronic liver disease since the time of the ancient Greeks.6 Silymarin is the most commonly used herbal product by individuals with chronic liver disease, and a recent publication from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial indicated that nearly one-third of patients in the trial were former or current users.7 Although the exact chemical composition of preparations varies, silymarin consists of a mixture of flavonoids termed flavonolignans.8 Results from laboratory, animal and clinical studies suggest that silymarin may have anti-inflammatory,9–11 anti-viral,11–14 antioxidant,10, 15 and antifibrotic effects in the liver.10, 16, 17 However, clinical efficacy, particularly in the context of chronic hepatitis C, remains unproven, and results from most previous studies, including randomised trials, are inconsistent.5, 6
As an a priori hypothesis, information on baseline silymarin use was collected as part of the HALT-C trial. In the current report, we examined the association of baseline silymarin use with subsequent liver disease progression in 1049 patients with advanced chronic hepatitis C.
Patients and methods
The HALT-C trial was designed to evaluate the efficacy of long-term treatment with low-dose peginterferon alpha-2a for patients with hepatitis C-related bridging fibrosis and cirrhosis who had failed standard of care peginterferon plus ribavirin therapy.18 Patients were recruited from ten US medical centres and met the following criteria: detectable HCV RNA; nonresponse to prior peginterferon/ribavirin therapy; hepatic bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage ≥2); and the absence of defined exclusion criteria (such as liver disease other than hepatitis C or history of hepatic decompensation or HCC).
Study design
A detailed description of the design of the HALT-C Trial is published.18 Patients whose previous failed treatment had not included peginterferon plus ribavirin were treated with this therapeutic combination as part of the ‘lead-in’ phase of the trial. If patients had detectable HCV RNA at 20 weeks of treatment, they were considered nonresponders and included in the randomised phase of the trial. Responders, who had undetectable HCV RNA at 20 weeks of treatment, received peginterferon plus ribavirin treatment for 48 weeks. Patients experiencing breakthrough, defined by detectable HCV RNA between 20 and 48 weeks of treatment, and patients who relapsed after completion of 48 weeks of therapy, could also enrol in the randomised phase of the trial. Finally, patients who upon recruitment had already failed peginterferon plus ribavirin therapy were immediately entered into the randomised phase of the trial (express patients).
During the randomised phase of the trial, patients were randomised to peginterferon alpha-2a 90 mcg weekly or no treatment. Liver biopsies were repeated 1.5 and 3.5 years after randomisation. A panel of twelve hepatic pathologists reviewed all biopsies and scored inflammation (0–18) and fibrosis (0–6) using the Ishak scoring system.19 As peginterferon therapy did not affect clinical outcome or histological progression,18 treated and untreated participant data from the randomised phase of the trial were combined.
Assessment of silymarin use
At baseline, trained study coordinators obtained patient medication use by way of an in-person interview. In addition to assessing prescription and nonprescription drugs, interviewers assessed CAM (herbal medications, dietary supplements and botanical products). Patients who used CAM at least once a week for 1 month or longer in their lives were defined as users. Duration of use was also recorded. To facilitate recall, patients were shown a card indicating 37 examples of herbal products in alphabetical order. Silymarin was one of these products. Patients also had the opportunity to indicate use of herbal products not listed on the card. Every 3 months after baseline, and as often as every 2 weeks during the lead-in phase, patients were asked whether they had stopped using any herbal products since their last visit or whether they were taking any new herbal products. Of 1050 randomised participants, we excluded one patient who lacked a medication record. We considered current users to be those using silymarin on the day of study randomisation. Former users could have used silymarin at any time prior to randomisation, including the lead-in phase. Duration of silymarin use included all months of use up to the day of randomisation. To analyse duration, we created a three level variable which included never users as the reference category. Months of use were then split at the median (16.6 months).
Morphometric image analysis of hepatic collagen content
Collagen in liver biopsy sections was stained with Sirius red and the degree of staining, which is proportional to the collagen content, was assessed using Image pro plus 6.0 imaging software (Media Cybernetics, Silver Spring, MD, USA) as previously described.20, 21 Sirius red values are expressed in arbitrary units, but reflect collagen content on a continuous scale. Analyses of collagen content were restricted to unfragmented biopsies with more than 10 mm2 of liver tissue in the section to avoid artefact and to reduce sampling variability. In total, 558 patients had morphometric image analysis performed on baseline biopsies, 550 patients had year 1.5 biopsies assessed by morphometry and 409 patients had year 3.5 biopsies analysed in this way. Of these patients, 183 had all three biopsies read.
Assessment of fibrosis and clinical outcomes
Patients were seen every 3 months in the randomised phase, at which point, complete blood counts, a liver chemistry panel and alpha-fetoprotein were tested at each clinical site. Patients also had at least one abdominal ultrasound examination every 12 months. Clinical outcomes included ascites, Child-Turcotte-Pugh score of ≥722 on two consecutive study visits, liver disease-related death, hepatic encephalopathy, hepatocellular carcinoma (HCC), spontaneous bacterial peritonitis, or variceal haemorrhage. Outcome reports were reviewed by an Outcomes Review Panel consisting of three investigators from the participating clinical centres. Participants with bridging fibrosis at baseline and a ≥2 point increase in Ishak fibrosis score (TPI) on either of the follow-up biopsies were considered to have fibrosis progression. Results are presented separately for clinical outcomes and for a two point increase in Ishak fibrosis score as well as for the two endpoints combined. HCC was diagnosed via ultrasound, AFP and histological confirmation as previously described.23
All details of this study were approved by the local Institutional Review Board at each participating institution, and all participants gave written informed consent.
Statistical analyses
We performed analyses using sas release 9.1 (SAS Institute, Cary, NC, USA). All tests were two-sided and an alpha level of <0.05 was considered statistically significant.
We tabulated baseline demographic, behavioural and clinical factors by categories of silymarin use (never, former, and current). Statistically significant variation across categories of silymarin use was assessed for categorical variables by the Mantel–Haenszel test for trend and for continuous variables with the Jonckheere–Terpstra test of trend.
Relative risks and 95% confidence intervals for the association of silymarin use with disease progression were calculated by use of Cox proportional hazards regression.24 Person-time was calculated from baseline to first outcome, end of study, or date of patient withdrawal. For clinical outcomes and the combined endpoint, follow-up time was up to 8.65 years. For TPI, follow-up was until first (1.5 years) or second biopsy (3.5 years). For clinical outcomes, Kaplan–Meier curves were generated for never, former and current silymarin users and were compared with the log-rank test.
Linear trend tests across increasing categories of silymarin use were performed by creating an ordinal variable for each category and entering the term as a continuous variable into the regression model. We tested the proportional hazards assumption by modelling interaction terms of time with trend variables for silymarin use. No significant deviations were found for silymarin use with either TPI or clinical outcomes; however, a significant deviation was found for HCC (P = 0.011).
Relative risks for liver disease progression were estimated from crude models and two different multivariate adjusted models. The first multivariate model included continuous age, lifetime alcohol use and coffee intake along with categorical variables for education (high school or less, some post high school, completed college), race/ethnicity (Caucasian, African American, Hispanic and other), gender, diabetes and ever use of other herbal products besides silymarin, such as green tea, garlic, ginseng, or echinacea. A second multivariate model was additionally adjusted for continuous mental and physical short-form (SF)-36 summary quality of life scores,25 and serological predictors of liver disease progression26– AST/ALT ratio, albumin, platelets, bilirubin, as well as categorical variables for cirrhosis status at baseline and presence or absence of oesophageal varices. For analyses of silymarin use during the trial, we updated silymarin use at the time of each follow-up biopsy. As for the main analyses, patients with a TPI at biopsy one (year 1.5) were censored at this time.
We assessed possible effect modification (interaction) by randomisation group, cirrhosis at baseline, median mental, and physical SF-36 quality of life scores and gender using stratification. Risk estimates did not vary by stratification group (P > 0.23 for all). Results stratified by cirrhosis at baseline are presented in the results section.
Finally, we analysed changes in morphometric collagen content across study biopsies using repeated analysis of variance, assuming an autoregressive covariance structure with the PROC MIXED function of sas 9.1. Again, analyses were restricted to patients who had not had an outcome prior to a particular scheduled study biopsy. Time (baseline, biopsy one, and biopsy two) and silymarin use (former and current) were included in the model as fixed effects. Adjustment for age and gender did not alter risk estimates and so were not included in the final models. Possible differences between the collagen content of biopsies taken from former or current silymarin users were compared with the collagen content of biopsies taken from never silymarin users by the Mann–Whitney test.
Results
At baseline, 17% (178/1049) of patients were former users of silymarin and 16% (170/1049) of patients were current users compared to 67% (701/1049) who reported never using silymarin (Table 1). The median duration of use for current users up to study entry was 35 months, whereas the median duration of use for former users was 6 months. Baseline silymarin use was associated with Caucasian race, completing college, male gender, lower prevalence of diabetes mellitus, higher lifetime alcohol and coffee consumption, and higher physical quality of life score. Silymarin was also modestly associated with a lower AST/ALT ratio and alkaline phosphatase levels and higher ALT, albumin levels, and prevalence of oesophageal varices (P < 0.05 for all). No association was observed for age, treatment group, patient cohort, body mass index, mental summary SF-36 score, serum AST, bilirubin, platelets, prothrombin time, HCV genotype or log RNA level, hepatic cirrhosis, collagen content, steatosis grade, or Ishak inflammation score.
At baseline, 621 patients had fibrosis and 428 patients had cirrhosis. During 4758 person-years of follow-up (median: 5.5 years per patient, interquartile range: 3.0–6.6 years), 384 patients had a two point increase in fibrosis score (TPI) from baseline or had a clinical outcome for liver disease. Combining these endpoints, we observed an inverse association between baseline silymarin use and liver disease progression (Table 2). In crude models, the relative risk (RR) associated with former use of silymarin was 0.87 (95% CI: 0.66–1.15), whereas the RR for current use was 0.73 (95% CI: 0.54–0.98; P-trend across categories = 0.029). Upon stratification by outcome, current silymarin use was associated with less TPI (RR for current vs. never use of silymarin, 0.54, 95% CI: 0.32–0.93; P-trend = 0.015), but had no association with clinical outcomes (RR for current vs. never, 0.86, 0.61–1.20; P-trend = 0.42). Multivariate adjustment for age, education, race/ethnicity, gender, lifetime alcohol use, diabetes, coffee intake, ever use of other herbal products besides silymarin, mental and physical quality of life scores, baseline cirrhosis, AST/ALT ratio, albumin, platelets, bilirubin and oesophageal varices only modestly affected risk estimates. After multivariate adjustment, the RR for current vs. never use of silymarin was 0.57 (95% CI: 0.33–1.00; P-trend = 0.042) for TPI and 1.09 (95% CI: 0.77–1.56; P-trend = 0.89) for clinical outcomes.
Duration of silymarin use, prior to baseline, was also assessed. Compared to never users, patients who used silymarin for up to the median duration (16.6 months) had an RR for TPI of 0.93 (0.58–1.51), whereas patients who used silymarin for greater than the median duration had an RR of 0.51 (95% CI: 0.30–0.90; P-trend = 0.026). The RRs for clinical outcomes for the same two categories of silymarin use were 0.86 (95% CI: 0.61–1.21) and 0.94 (95% CI: 0.66–1.35; P-trend = 0.57) respectively (data not shown in table).
In addition to silymarin use at baseline, we examined silymarin use over the course of the study. At the time of the second biopsy, three and a half years after randomisation, 69% of baseline users continued to use silymarin (88/128), whereas only 3% of baseline non-users (15/477) had started use. The risk of TPI among patients with fibrosis who continued to use silymarin throughout the study was 0.55 (95% CI: 0.29–1.03; 68 patients, 11 events), whereas the risk of TPI among patients who stopped using silymarin during follow-up was 0.66 (95% CI: 0.23–1.87; 20 patients, 4 events) (data not shown in table).
Silymarin was the most commonly used herbal product in the HALT-C trial. Fourteen percent of patients used an herbal product other than silymarin (n = 142). Use of a nonsilymarin herbal product had no association with either TPI (0.92, 95% CI: 0.57–1.48) or clinical outcomes (0.87, 95% CI: 0.60–1.25) (data not shown in table).
Among those with fibrosis, comparing current users of silymarin with never users, the RR for TPI was 0.19 (95% CI: 0.02–2.05; 16 events) for patients with an Ishak score of 2 at baseline, 0.48 (95% CI: 0.22–1.04; 87 events) for patients with an Ishak score of 3 at baseline, and 1.04 (95% CI: 0.37–2.90; 49 events) for patients with an Ishak score of 4 at baseline (data not shown in table). For those with fibrosis at baseline, we also examined the distribution of Ishak scores at year 1.5 and year 3.5 protocol biopsies. The distribution of Ishak scores was similar between former and never silymarin users for both biopsies (P > 0.30). For current silymarin users vs. never silymarin users, P-values for differences in the distribution of Ishak scores were 0.097 and 0.0059, for year 1.5 and year 3.5 biopsies respectively (Figure 1).
No association for clinical outcomes was found for those with either fibrosis or cirrhosis at baseline (RR for current use vs. never use, 1.36, 95% CI: 0.74–2.50, P-trend = 0.32, 98 events and 0.97, 95% CI: 0.61–1.53, P-trend = 0.41, 176 events, for fibrosis and cirrhosis respectively). The association between silymarin and clinical outcomes was also similar for outcomes occurring during years zero through four (RR for current vs. never use, 1.20, 95% CI: 0.78–1.86; P-trend = 0.85, 173 events) and five through eight of follow-up (0.88, 95% CI: 0.47–1.63; P-trend = 0.88, 101 events) (data not shown in table). Kaplan–Meier curves for clinical outcomes among current, former and never users of silymarin were similar (Figure 2; P = 0.657). In a secondary analysis of 88 incident cases of HCC, compared to never use, the RR for former and current users was 1.15 (95% CI: 0.62–2.13) and 1.60 (95% CI: 0.93–2.76) respectively. This possible effect was restricted to events occurring during the first 4 years (HR: 1.96, 95% CI: 0.95–4.05; 47 events), but not years five-eight of follow-up (HR: 1.26, 95% CI: 0.54–2.94; 41 events).
Finally, we examined the association between silymarin use and biopsy collagen content as measured by morphometric image analysis (Table 3). The collagen content of each study biopsy appeared generally similar in former and never users of silymarin. But, the study biopsies of baseline silymarin users tended to have a lower collagen content than study biopsies of never users. For example, the mean collagen content on the year 3.5 biopsy was 0.071 (standard deviation = 0.069) among current silymarin users and 0.090 (standard deviation = 0.085) among never users, P-value = 0.061. The overall P-value comparing the change in collagen content across repeated biopsies in baseline silymarin users relative to never users was 0.037. After stratification by baseline cirrhosis status, the association between silymarin use with change in collagen content across repeated study biopsies persisted in both patients with fibrosis (overall P-value = 0.034) and those with cirrhosis (overall P-value = 0.011) at baseline.
Discussion
In a large prospective cohort of individuals with advanced hepatitis C- related chronic liver disease, no clinical benefit was found for current silymarin use at baseline. In addition, we observed a nonsignificant increase in HCC risk among current silymarin users, which was present only in the first 4 years of follow-up. Baseline silymarin use was associated with less liver disease progression as measured by a two-point increase in Ishak fibrosis score as well as in the distribution of fibrosis scores in follow-up biopsies. A dose–response with duration of use was observed. Current use of silymarin at baseline, but not former use prior to baseline, was associated inversely with biopsy collagen content, regardless of whether patients had fibrosis or cirrhosis.
Silymarin has been used to treat liver disease for thousands of years.6, 27 Furthermore, results from animal, in vitro and clinical studies suggest that silymarin has possible anti-inflammatory,9–11 anti-viral,11–14 antioxidant10, 15 and antifibrotic effects.10, 16, 17 Yet, few clinical and observational studies have evaluated the effect of silymarin on liver disease progression and clinical outcomes in humans. Previous studies had small size, limited power to detect associations, and yielded mixed results.6, 27 For example, one trial of 170 patients with alcohol-related liver disease showed an effect of silymarin on survival,28 whereas a second trial of 200 patients showed similar survival rates in the randomised and control arms.29 Even fewer data are available for hepatitis C-related liver disease. Data from an Egyptian randomised trial of 141 patients showed no effect for silymarin on outcomes.30, 31
It is not clear why silymarin was associated with a reduction in rate of fibrosis progression, but not with clinical outcomes in our study. One possibility is that in order to exert an effect, silymarin must be used early in the disease progression process. In support of this hypothesis, silymarin seemed to have an effect on histological progression if patients had an Ishak score of 2 or 3 at baseline, but no effect on individuals with a score of 4 at baseline. On the other hand, silymarin had no effect on clinical outcomes for individuals with either cirrhosis or fibrosis at baseline, or for outcomes occurring during the first 4 years, or years five-eight of follow-up. It remains possible, however, that follow-up was too short to see an effect on clinical outcomes.
Fibrosis progression is not the sole determinant of subsequent decompensation or complications of portal hypertension. As such, it is also possible that silymarin does not have a beneficial effect on other determinants of clinical outcomes.32 Alternatively, differences between histological progression and clinical outcomes could simply reflect chance.
Strengths of our study include assessment of silymarin use before disease progression, the large number of patients with advanced hepatitis C-related liver disease, comprehensive assessment of clinical, demographic and lifestyle information, and careful assessment of clinical and histological outcomes. The major limitation was a complete lack of information on the amount of silymarin patients used per day. We also lacked information on how silymarin was prepared. Patients in the HALT-C trial probably used many different dosages and formulations of silymarin and even for individual patients, preparations probably varied day by day and week by week. Furthermore, it is unlikely that patients would have ingested pharmacological doses of silymarin as have shown effect in vitro, clinical, and animal studies. For example, a recent study of 36 patients observed an effect of intravenously (i.v.) administered silymarin (as silibinin) on hepatitis C viral level,14 although a study with similar dosing of orally administered silymarin showed no effect.33 Most likely, patients in HALT-C used less silymarin than those in the i.v. study. Further complicating interpretation is that the pharmacokinetics of silymarin may be altered by fibrosis. A recent study administered a standard silymarin dose to cirrhotics and healthy volunteers. In response to silymarin treatment, serum flavonolignans were higher in the cirrhotic volunteers.34 Finally, not all study biopsies were large enough to have morphometric analysis performed, a potential source of selection bias. Indeed, patients with cirrhosis were less likely to receive all biopsies.21 Yet, as we observed an apparent inverse association between silymarin use and collagen content, such a bias, if anything, would probably attenuate the observed association between silymarin use and collagen content.
In the HALT-C trial, use of silymarin was associated with Caucasian race, completing college and a higher SF-36 physical quality of life score, suggesting that silymarin use might be a marker for a large number of other lifestyle factors. We adjusted our risk estimates for these and other possible confounders. After adjustment, risk estimates were only modestly altered. In addition, the observed effect of silymarin does not simply reflect a propensity to use herbal products. Using herbal products, other than silymarin, had no association with either histological progression or clinical outcomes in our study. Nevertheless, as an observational study, the inverse association observed between silymarin use and histological progression could reflect another exposure or chance. We did not have any information on brand or dosage of silymarin. However, this limitation is reflective of the difficulty in detailing patient behaviour outside controlled studies. Many, if not most, patients with currently incurable liver disease seek alternative, unapproved therapies that cannot be easily quantified, yet deserve evaluation.
In summary, among individuals with advanced hepatitis-C-associated liver disease, we observed an inverse association between silymarin use and the progression of liver disease from fibrosis to cirrhosis, but no evidence for an effect on clinical outcomes. As our results are from an observational study, it is possible that the observed beneficial effect on liver disease progression is due to chance. Future studies with a comprehensive assessment of silymarin dose are needed to replicate these findings. Nevertheless, our results provide support for conducting additional studies of silymarin, including intervention trials with defined dosage regimens and standard silymarin product. Such studies would be most appropriate for patients who have not responded to or are not candidates for anti-viral therapy and have limited other treatment options. Importantly, our results do not support the use of ad hoc dosing of silymarin by patients with chronic liver disease.
Acknowledgements
Declaration of personal interests: None. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows:
University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN.
University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP.
Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN.
Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Jules L. Dienstag, MD, Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark.
University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01), Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN.
University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN.
University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH.
University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN.
University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Anna S. Lok, MD, Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS.
Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: Marc G. Ghany, MD, T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN.
National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD.
University of Washington, Seattle, WA: (Contract N01-DK-9-2318) David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed.
New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, Margaret C. Bell, MS, MPH.
Armed Forces Institute of Pathology, Washington, DC: Fanny Monge, Michelle Parks.
Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD.
Declaration of funding interests: This study was funded in part by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the Acknowledgement). This research was also supported in part by the Intramural Research Program of the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.
References
1 . The global burden of hepatitis C. Liver Int 2009; 29(Suppl. 1): 74–81.
17 , , . Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996; 23: 749–54.
Volume 33, Issue 1, pages 127–137, January 2011
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Aliment Pharmacol Ther 2011; 33: 127–137
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Introduction
An estimated 130–170 million individuals are chronically infected with hepatitis C virus worldwide.1 Pegylated interferon and ribavirin treatment results in an approximate sustained virological response rate of 55%.2, 3 However, individuals who fail to respond or who are unable to tolerate treatment have few additional options. As such, many patients have turned to complementary and alternative medications (CAM) instead of, or in addition to, standard therapy.4, 5
An extract of the milk thistle plant, silymarin (Silybum marianum), has been used to treat chronic liver disease since the time of the ancient Greeks.6 Silymarin is the most commonly used herbal product by individuals with chronic liver disease, and a recent publication from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial indicated that nearly one-third of patients in the trial were former or current users.7 Although the exact chemical composition of preparations varies, silymarin consists of a mixture of flavonoids termed flavonolignans.8 Results from laboratory, animal and clinical studies suggest that silymarin may have anti-inflammatory,9–11 anti-viral,11–14 antioxidant,10, 15 and antifibrotic effects in the liver.10, 16, 17 However, clinical efficacy, particularly in the context of chronic hepatitis C, remains unproven, and results from most previous studies, including randomised trials, are inconsistent.5, 6
As an a priori hypothesis, information on baseline silymarin use was collected as part of the HALT-C trial. In the current report, we examined the association of baseline silymarin use with subsequent liver disease progression in 1049 patients with advanced chronic hepatitis C.
Patients and methods
The HALT-C trial was designed to evaluate the efficacy of long-term treatment with low-dose peginterferon alpha-2a for patients with hepatitis C-related bridging fibrosis and cirrhosis who had failed standard of care peginterferon plus ribavirin therapy.18 Patients were recruited from ten US medical centres and met the following criteria: detectable HCV RNA; nonresponse to prior peginterferon/ribavirin therapy; hepatic bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage ≥2); and the absence of defined exclusion criteria (such as liver disease other than hepatitis C or history of hepatic decompensation or HCC).
Study design
A detailed description of the design of the HALT-C Trial is published.18 Patients whose previous failed treatment had not included peginterferon plus ribavirin were treated with this therapeutic combination as part of the ‘lead-in’ phase of the trial. If patients had detectable HCV RNA at 20 weeks of treatment, they were considered nonresponders and included in the randomised phase of the trial. Responders, who had undetectable HCV RNA at 20 weeks of treatment, received peginterferon plus ribavirin treatment for 48 weeks. Patients experiencing breakthrough, defined by detectable HCV RNA between 20 and 48 weeks of treatment, and patients who relapsed after completion of 48 weeks of therapy, could also enrol in the randomised phase of the trial. Finally, patients who upon recruitment had already failed peginterferon plus ribavirin therapy were immediately entered into the randomised phase of the trial (express patients).
During the randomised phase of the trial, patients were randomised to peginterferon alpha-2a 90 mcg weekly or no treatment. Liver biopsies were repeated 1.5 and 3.5 years after randomisation. A panel of twelve hepatic pathologists reviewed all biopsies and scored inflammation (0–18) and fibrosis (0–6) using the Ishak scoring system.19 As peginterferon therapy did not affect clinical outcome or histological progression,18 treated and untreated participant data from the randomised phase of the trial were combined.
Assessment of silymarin use
At baseline, trained study coordinators obtained patient medication use by way of an in-person interview. In addition to assessing prescription and nonprescription drugs, interviewers assessed CAM (herbal medications, dietary supplements and botanical products). Patients who used CAM at least once a week for 1 month or longer in their lives were defined as users. Duration of use was also recorded. To facilitate recall, patients were shown a card indicating 37 examples of herbal products in alphabetical order. Silymarin was one of these products. Patients also had the opportunity to indicate use of herbal products not listed on the card. Every 3 months after baseline, and as often as every 2 weeks during the lead-in phase, patients were asked whether they had stopped using any herbal products since their last visit or whether they were taking any new herbal products. Of 1050 randomised participants, we excluded one patient who lacked a medication record. We considered current users to be those using silymarin on the day of study randomisation. Former users could have used silymarin at any time prior to randomisation, including the lead-in phase. Duration of silymarin use included all months of use up to the day of randomisation. To analyse duration, we created a three level variable which included never users as the reference category. Months of use were then split at the median (16.6 months).
Morphometric image analysis of hepatic collagen content
Collagen in liver biopsy sections was stained with Sirius red and the degree of staining, which is proportional to the collagen content, was assessed using Image pro plus 6.0 imaging software (Media Cybernetics, Silver Spring, MD, USA) as previously described.20, 21 Sirius red values are expressed in arbitrary units, but reflect collagen content on a continuous scale. Analyses of collagen content were restricted to unfragmented biopsies with more than 10 mm2 of liver tissue in the section to avoid artefact and to reduce sampling variability. In total, 558 patients had morphometric image analysis performed on baseline biopsies, 550 patients had year 1.5 biopsies assessed by morphometry and 409 patients had year 3.5 biopsies analysed in this way. Of these patients, 183 had all three biopsies read.
Assessment of fibrosis and clinical outcomes
Patients were seen every 3 months in the randomised phase, at which point, complete blood counts, a liver chemistry panel and alpha-fetoprotein were tested at each clinical site. Patients also had at least one abdominal ultrasound examination every 12 months. Clinical outcomes included ascites, Child-Turcotte-Pugh score of ≥722 on two consecutive study visits, liver disease-related death, hepatic encephalopathy, hepatocellular carcinoma (HCC), spontaneous bacterial peritonitis, or variceal haemorrhage. Outcome reports were reviewed by an Outcomes Review Panel consisting of three investigators from the participating clinical centres. Participants with bridging fibrosis at baseline and a ≥2 point increase in Ishak fibrosis score (TPI) on either of the follow-up biopsies were considered to have fibrosis progression. Results are presented separately for clinical outcomes and for a two point increase in Ishak fibrosis score as well as for the two endpoints combined. HCC was diagnosed via ultrasound, AFP and histological confirmation as previously described.23
All details of this study were approved by the local Institutional Review Board at each participating institution, and all participants gave written informed consent.
Statistical analyses
We performed analyses using sas release 9.1 (SAS Institute, Cary, NC, USA). All tests were two-sided and an alpha level of <0.05 was considered statistically significant.
We tabulated baseline demographic, behavioural and clinical factors by categories of silymarin use (never, former, and current). Statistically significant variation across categories of silymarin use was assessed for categorical variables by the Mantel–Haenszel test for trend and for continuous variables with the Jonckheere–Terpstra test of trend.
Relative risks and 95% confidence intervals for the association of silymarin use with disease progression were calculated by use of Cox proportional hazards regression.24 Person-time was calculated from baseline to first outcome, end of study, or date of patient withdrawal. For clinical outcomes and the combined endpoint, follow-up time was up to 8.65 years. For TPI, follow-up was until first (1.5 years) or second biopsy (3.5 years). For clinical outcomes, Kaplan–Meier curves were generated for never, former and current silymarin users and were compared with the log-rank test.
Linear trend tests across increasing categories of silymarin use were performed by creating an ordinal variable for each category and entering the term as a continuous variable into the regression model. We tested the proportional hazards assumption by modelling interaction terms of time with trend variables for silymarin use. No significant deviations were found for silymarin use with either TPI or clinical outcomes; however, a significant deviation was found for HCC (P = 0.011).
Relative risks for liver disease progression were estimated from crude models and two different multivariate adjusted models. The first multivariate model included continuous age, lifetime alcohol use and coffee intake along with categorical variables for education (high school or less, some post high school, completed college), race/ethnicity (Caucasian, African American, Hispanic and other), gender, diabetes and ever use of other herbal products besides silymarin, such as green tea, garlic, ginseng, or echinacea. A second multivariate model was additionally adjusted for continuous mental and physical short-form (SF)-36 summary quality of life scores,25 and serological predictors of liver disease progression26– AST/ALT ratio, albumin, platelets, bilirubin, as well as categorical variables for cirrhosis status at baseline and presence or absence of oesophageal varices. For analyses of silymarin use during the trial, we updated silymarin use at the time of each follow-up biopsy. As for the main analyses, patients with a TPI at biopsy one (year 1.5) were censored at this time.
We assessed possible effect modification (interaction) by randomisation group, cirrhosis at baseline, median mental, and physical SF-36 quality of life scores and gender using stratification. Risk estimates did not vary by stratification group (P > 0.23 for all). Results stratified by cirrhosis at baseline are presented in the results section.
Finally, we analysed changes in morphometric collagen content across study biopsies using repeated analysis of variance, assuming an autoregressive covariance structure with the PROC MIXED function of sas 9.1. Again, analyses were restricted to patients who had not had an outcome prior to a particular scheduled study biopsy. Time (baseline, biopsy one, and biopsy two) and silymarin use (former and current) were included in the model as fixed effects. Adjustment for age and gender did not alter risk estimates and so were not included in the final models. Possible differences between the collagen content of biopsies taken from former or current silymarin users were compared with the collagen content of biopsies taken from never silymarin users by the Mann–Whitney test.
Results
At baseline, 17% (178/1049) of patients were former users of silymarin and 16% (170/1049) of patients were current users compared to 67% (701/1049) who reported never using silymarin (Table 1). The median duration of use for current users up to study entry was 35 months, whereas the median duration of use for former users was 6 months. Baseline silymarin use was associated with Caucasian race, completing college, male gender, lower prevalence of diabetes mellitus, higher lifetime alcohol and coffee consumption, and higher physical quality of life score. Silymarin was also modestly associated with a lower AST/ALT ratio and alkaline phosphatase levels and higher ALT, albumin levels, and prevalence of oesophageal varices (P < 0.05 for all). No association was observed for age, treatment group, patient cohort, body mass index, mental summary SF-36 score, serum AST, bilirubin, platelets, prothrombin time, HCV genotype or log RNA level, hepatic cirrhosis, collagen content, steatosis grade, or Ishak inflammation score.
At baseline, 621 patients had fibrosis and 428 patients had cirrhosis. During 4758 person-years of follow-up (median: 5.5 years per patient, interquartile range: 3.0–6.6 years), 384 patients had a two point increase in fibrosis score (TPI) from baseline or had a clinical outcome for liver disease. Combining these endpoints, we observed an inverse association between baseline silymarin use and liver disease progression (Table 2). In crude models, the relative risk (RR) associated with former use of silymarin was 0.87 (95% CI: 0.66–1.15), whereas the RR for current use was 0.73 (95% CI: 0.54–0.98; P-trend across categories = 0.029). Upon stratification by outcome, current silymarin use was associated with less TPI (RR for current vs. never use of silymarin, 0.54, 95% CI: 0.32–0.93; P-trend = 0.015), but had no association with clinical outcomes (RR for current vs. never, 0.86, 0.61–1.20; P-trend = 0.42). Multivariate adjustment for age, education, race/ethnicity, gender, lifetime alcohol use, diabetes, coffee intake, ever use of other herbal products besides silymarin, mental and physical quality of life scores, baseline cirrhosis, AST/ALT ratio, albumin, platelets, bilirubin and oesophageal varices only modestly affected risk estimates. After multivariate adjustment, the RR for current vs. never use of silymarin was 0.57 (95% CI: 0.33–1.00; P-trend = 0.042) for TPI and 1.09 (95% CI: 0.77–1.56; P-trend = 0.89) for clinical outcomes.
Duration of silymarin use, prior to baseline, was also assessed. Compared to never users, patients who used silymarin for up to the median duration (16.6 months) had an RR for TPI of 0.93 (0.58–1.51), whereas patients who used silymarin for greater than the median duration had an RR of 0.51 (95% CI: 0.30–0.90; P-trend = 0.026). The RRs for clinical outcomes for the same two categories of silymarin use were 0.86 (95% CI: 0.61–1.21) and 0.94 (95% CI: 0.66–1.35; P-trend = 0.57) respectively (data not shown in table).
In addition to silymarin use at baseline, we examined silymarin use over the course of the study. At the time of the second biopsy, three and a half years after randomisation, 69% of baseline users continued to use silymarin (88/128), whereas only 3% of baseline non-users (15/477) had started use. The risk of TPI among patients with fibrosis who continued to use silymarin throughout the study was 0.55 (95% CI: 0.29–1.03; 68 patients, 11 events), whereas the risk of TPI among patients who stopped using silymarin during follow-up was 0.66 (95% CI: 0.23–1.87; 20 patients, 4 events) (data not shown in table).
Silymarin was the most commonly used herbal product in the HALT-C trial. Fourteen percent of patients used an herbal product other than silymarin (n = 142). Use of a nonsilymarin herbal product had no association with either TPI (0.92, 95% CI: 0.57–1.48) or clinical outcomes (0.87, 95% CI: 0.60–1.25) (data not shown in table).
Among those with fibrosis, comparing current users of silymarin with never users, the RR for TPI was 0.19 (95% CI: 0.02–2.05; 16 events) for patients with an Ishak score of 2 at baseline, 0.48 (95% CI: 0.22–1.04; 87 events) for patients with an Ishak score of 3 at baseline, and 1.04 (95% CI: 0.37–2.90; 49 events) for patients with an Ishak score of 4 at baseline (data not shown in table). For those with fibrosis at baseline, we also examined the distribution of Ishak scores at year 1.5 and year 3.5 protocol biopsies. The distribution of Ishak scores was similar between former and never silymarin users for both biopsies (P > 0.30). For current silymarin users vs. never silymarin users, P-values for differences in the distribution of Ishak scores were 0.097 and 0.0059, for year 1.5 and year 3.5 biopsies respectively (Figure 1).
No association for clinical outcomes was found for those with either fibrosis or cirrhosis at baseline (RR for current use vs. never use, 1.36, 95% CI: 0.74–2.50, P-trend = 0.32, 98 events and 0.97, 95% CI: 0.61–1.53, P-trend = 0.41, 176 events, for fibrosis and cirrhosis respectively). The association between silymarin and clinical outcomes was also similar for outcomes occurring during years zero through four (RR for current vs. never use, 1.20, 95% CI: 0.78–1.86; P-trend = 0.85, 173 events) and five through eight of follow-up (0.88, 95% CI: 0.47–1.63; P-trend = 0.88, 101 events) (data not shown in table). Kaplan–Meier curves for clinical outcomes among current, former and never users of silymarin were similar (Figure 2; P = 0.657). In a secondary analysis of 88 incident cases of HCC, compared to never use, the RR for former and current users was 1.15 (95% CI: 0.62–2.13) and 1.60 (95% CI: 0.93–2.76) respectively. This possible effect was restricted to events occurring during the first 4 years (HR: 1.96, 95% CI: 0.95–4.05; 47 events), but not years five-eight of follow-up (HR: 1.26, 95% CI: 0.54–2.94; 41 events).
Finally, we examined the association between silymarin use and biopsy collagen content as measured by morphometric image analysis (Table 3). The collagen content of each study biopsy appeared generally similar in former and never users of silymarin. But, the study biopsies of baseline silymarin users tended to have a lower collagen content than study biopsies of never users. For example, the mean collagen content on the year 3.5 biopsy was 0.071 (standard deviation = 0.069) among current silymarin users and 0.090 (standard deviation = 0.085) among never users, P-value = 0.061. The overall P-value comparing the change in collagen content across repeated biopsies in baseline silymarin users relative to never users was 0.037. After stratification by baseline cirrhosis status, the association between silymarin use with change in collagen content across repeated study biopsies persisted in both patients with fibrosis (overall P-value = 0.034) and those with cirrhosis (overall P-value = 0.011) at baseline.
Discussion
In a large prospective cohort of individuals with advanced hepatitis C- related chronic liver disease, no clinical benefit was found for current silymarin use at baseline. In addition, we observed a nonsignificant increase in HCC risk among current silymarin users, which was present only in the first 4 years of follow-up. Baseline silymarin use was associated with less liver disease progression as measured by a two-point increase in Ishak fibrosis score as well as in the distribution of fibrosis scores in follow-up biopsies. A dose–response with duration of use was observed. Current use of silymarin at baseline, but not former use prior to baseline, was associated inversely with biopsy collagen content, regardless of whether patients had fibrosis or cirrhosis.
Silymarin has been used to treat liver disease for thousands of years.6, 27 Furthermore, results from animal, in vitro and clinical studies suggest that silymarin has possible anti-inflammatory,9–11 anti-viral,11–14 antioxidant10, 15 and antifibrotic effects.10, 16, 17 Yet, few clinical and observational studies have evaluated the effect of silymarin on liver disease progression and clinical outcomes in humans. Previous studies had small size, limited power to detect associations, and yielded mixed results.6, 27 For example, one trial of 170 patients with alcohol-related liver disease showed an effect of silymarin on survival,28 whereas a second trial of 200 patients showed similar survival rates in the randomised and control arms.29 Even fewer data are available for hepatitis C-related liver disease. Data from an Egyptian randomised trial of 141 patients showed no effect for silymarin on outcomes.30, 31
It is not clear why silymarin was associated with a reduction in rate of fibrosis progression, but not with clinical outcomes in our study. One possibility is that in order to exert an effect, silymarin must be used early in the disease progression process. In support of this hypothesis, silymarin seemed to have an effect on histological progression if patients had an Ishak score of 2 or 3 at baseline, but no effect on individuals with a score of 4 at baseline. On the other hand, silymarin had no effect on clinical outcomes for individuals with either cirrhosis or fibrosis at baseline, or for outcomes occurring during the first 4 years, or years five-eight of follow-up. It remains possible, however, that follow-up was too short to see an effect on clinical outcomes.
Fibrosis progression is not the sole determinant of subsequent decompensation or complications of portal hypertension. As such, it is also possible that silymarin does not have a beneficial effect on other determinants of clinical outcomes.32 Alternatively, differences between histological progression and clinical outcomes could simply reflect chance.
Strengths of our study include assessment of silymarin use before disease progression, the large number of patients with advanced hepatitis C-related liver disease, comprehensive assessment of clinical, demographic and lifestyle information, and careful assessment of clinical and histological outcomes. The major limitation was a complete lack of information on the amount of silymarin patients used per day. We also lacked information on how silymarin was prepared. Patients in the HALT-C trial probably used many different dosages and formulations of silymarin and even for individual patients, preparations probably varied day by day and week by week. Furthermore, it is unlikely that patients would have ingested pharmacological doses of silymarin as have shown effect in vitro, clinical, and animal studies. For example, a recent study of 36 patients observed an effect of intravenously (i.v.) administered silymarin (as silibinin) on hepatitis C viral level,14 although a study with similar dosing of orally administered silymarin showed no effect.33 Most likely, patients in HALT-C used less silymarin than those in the i.v. study. Further complicating interpretation is that the pharmacokinetics of silymarin may be altered by fibrosis. A recent study administered a standard silymarin dose to cirrhotics and healthy volunteers. In response to silymarin treatment, serum flavonolignans were higher in the cirrhotic volunteers.34 Finally, not all study biopsies were large enough to have morphometric analysis performed, a potential source of selection bias. Indeed, patients with cirrhosis were less likely to receive all biopsies.21 Yet, as we observed an apparent inverse association between silymarin use and collagen content, such a bias, if anything, would probably attenuate the observed association between silymarin use and collagen content.
In the HALT-C trial, use of silymarin was associated with Caucasian race, completing college and a higher SF-36 physical quality of life score, suggesting that silymarin use might be a marker for a large number of other lifestyle factors. We adjusted our risk estimates for these and other possible confounders. After adjustment, risk estimates were only modestly altered. In addition, the observed effect of silymarin does not simply reflect a propensity to use herbal products. Using herbal products, other than silymarin, had no association with either histological progression or clinical outcomes in our study. Nevertheless, as an observational study, the inverse association observed between silymarin use and histological progression could reflect another exposure or chance. We did not have any information on brand or dosage of silymarin. However, this limitation is reflective of the difficulty in detailing patient behaviour outside controlled studies. Many, if not most, patients with currently incurable liver disease seek alternative, unapproved therapies that cannot be easily quantified, yet deserve evaluation.
In summary, among individuals with advanced hepatitis-C-associated liver disease, we observed an inverse association between silymarin use and the progression of liver disease from fibrosis to cirrhosis, but no evidence for an effect on clinical outcomes. As our results are from an observational study, it is possible that the observed beneficial effect on liver disease progression is due to chance. Future studies with a comprehensive assessment of silymarin dose are needed to replicate these findings. Nevertheless, our results provide support for conducting additional studies of silymarin, including intervention trials with defined dosage regimens and standard silymarin product. Such studies would be most appropriate for patients who have not responded to or are not candidates for anti-viral therapy and have limited other treatment options. Importantly, our results do not support the use of ad hoc dosing of silymarin by patients with chronic liver disease.
Acknowledgements
Declaration of personal interests: None. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows:
University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN.
University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP.
Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN.
Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Jules L. Dienstag, MD, Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark.
University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01), Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN.
University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN.
University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH.
University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN.
University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Anna S. Lok, MD, Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS.
Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: Marc G. Ghany, MD, T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN.
National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD.
University of Washington, Seattle, WA: (Contract N01-DK-9-2318) David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed.
New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, Margaret C. Bell, MS, MPH.
Armed Forces Institute of Pathology, Washington, DC: Fanny Monge, Michelle Parks.
Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD.
Declaration of funding interests: This study was funded in part by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the Acknowledgement). This research was also supported in part by the Intramural Research Program of the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.
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8 , , , . Separation and characterization of active flavonolignans of Silybum marianum by liquid chromatography connected with hybrid ion-trap and time-of-flight mass spectrometry (LC-MS/IT-TOF). J Nat Prod 2007; 70: 1424–8.
9 , , , et al. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology 2010; 138: 671–81.
10 , , , et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol 2009; 50: 1102–11.
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13 , , , et al. Effects of silymarin on hepatitis C virus and haem oxygenase-1 gene expression in human hepatoma cells. Liver Int 2009; 29: 366–73. 14 , , , et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135: 1561–7.
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New study upends thinking about how liver disease develops
December 20, 2010
In the latest of a series of related papers, researchers at the University of California, San Diego School of Medicine, with colleagues in Austria and elsewhere, present a new and more definitive explanation of how fibrotic cells form, multiply and eventually destroy the human liver, resulting in cirrhosis. In doing so, the findings upend the standing of a long-presumed marker for multiple fibrotic diseases and reveal the existence of a previously unknown kind of inflammatory white blood cell.
The results are published in this week’s early online edition of the Proceedings of the National Academy of Sciences.
In all types of chronic diseases, healthy, functioning tissues are progressively replaced by fibrous scarring, which renders the tissues or larger organ increasingly dysfunctional until, eventually, it fails. The process is called fibrosis. In the human liver, the end result is cirrhosis, the 12th leading cause of death by disease in the United States with roughly 27,000 deaths annually. Fibrosis occurs in other organs as well, such as the heart, kidneys and lungs, with comparable deadly effect.
Scientists do not fully understand the process of fibrosis, particularly how problematic fibroblast cells are created. For years, conventional wisdom has posited that fibroblasts are likely to be transformed epithelial cells, a conversion called “epithelial to mesenchymal transition” or EMT. A protein called fibroblast-specific protein 1 (FSP1) has long been considered to be a reliable indicator of fibroblasts in injured organs undergoing tissue remodeling and has been broadly used to identify the presence of fibrotic disease.
The new research undermines the validity of prevailing assumptions about EMT and FSP1, but also opens the door to new avenues of investigation that could ultimately lead to improved detection and treatment of cirrhosis and similar conditions.
“This work, along with earlier papers, puts into question a whole area of research — at least in terms of the liver” said David Brenner, MD, Vice Chancellor for Health Sciences, dean of the UC San Diego School of Medicine and co-author of the paper. “The old evidence and assumptions about the source of fibroblasts and the role of FSP1 as a marker are not valid.”
Specifically, in experiments using cell cultures, human liver samples and mouse models, the researchers found no evidence of EMT — that transformed epithelial cells became liver fibroblasts. Rather, endogenous stellate cells appear to be the culprit, though the scientists note many types of cells seem to contribute, directly or indirectly, to liver fibrosis.
Likewise, experiments proved FSP1 to be an unreliable marker for fibrosis. Cells containing FSP1 increased in human and experimental liver disease and in liver cancer, but researchers found that liver fibroblasts do not express the protein, nor do hepatic stellate cells — a major cell type involved in liver fibrosis. Similarly, FSP1 was determined not to be a marker for myofibroblasts (a fibroblast with some properties of a smooth muscle cell) or any precursors of myofibroblasts.
“There have been hundreds of papers based on FSP1 as a marker,” said Brenner. “That thinking now seems to have been a mistake. One of the take-home messages of this paper is that FSP1 clearly can’t be reliably used as a marker.”
On the other hand, the scientists discovered that FSP1 is a consistent marker for a previously unknown subset of inflammatory white blood cells or macrophages found in injured livers. The protein appears to also perform biological functions in the macrophages, though these remain to be determined.
“It’s a whole new class of monocytes,” said Brenner. “We don’t know what they do, but they’re worth investigating.”
Co-authors of the study are Christoph H. Osterreicher of the Department of Medicine, Laboratory of Gene Regulation and Signal Transduction and Department of Pharmacology, all at UC San Diego, and of the Institute of Pharmacology, Center for Physiology and Pharmacology and the Department of Internal Medicine, Division of Gastroenterology at Medical University of Vienna in Austria; Melitta Penz-Osterreicher of the Department of Medicine at UC San Diego and the Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna; Sergei I. Grivennikov and Monica Guma of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, UC San Diego; Ekaterina K. Koltsova of the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology; Christian Datz of the Department of Internal Medicine, General Hospital Oberndorf in Austria; Roman Sasik and Gary Hardiman of Biomedical Genomics Microarray Facility, Department of Medicine, UC San Diego; and Michael Karin of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology at UC San Diego.
Source
In the latest of a series of related papers, researchers at the University of California, San Diego School of Medicine, with colleagues in Austria and elsewhere, present a new and more definitive explanation of how fibrotic cells form, multiply and eventually destroy the human liver, resulting in cirrhosis. In doing so, the findings upend the standing of a long-presumed marker for multiple fibrotic diseases and reveal the existence of a previously unknown kind of inflammatory white blood cell.
The results are published in this week’s early online edition of the Proceedings of the National Academy of Sciences.
In all types of chronic diseases, healthy, functioning tissues are progressively replaced by fibrous scarring, which renders the tissues or larger organ increasingly dysfunctional until, eventually, it fails. The process is called fibrosis. In the human liver, the end result is cirrhosis, the 12th leading cause of death by disease in the United States with roughly 27,000 deaths annually. Fibrosis occurs in other organs as well, such as the heart, kidneys and lungs, with comparable deadly effect.
Scientists do not fully understand the process of fibrosis, particularly how problematic fibroblast cells are created. For years, conventional wisdom has posited that fibroblasts are likely to be transformed epithelial cells, a conversion called “epithelial to mesenchymal transition” or EMT. A protein called fibroblast-specific protein 1 (FSP1) has long been considered to be a reliable indicator of fibroblasts in injured organs undergoing tissue remodeling and has been broadly used to identify the presence of fibrotic disease.
The new research undermines the validity of prevailing assumptions about EMT and FSP1, but also opens the door to new avenues of investigation that could ultimately lead to improved detection and treatment of cirrhosis and similar conditions.
“This work, along with earlier papers, puts into question a whole area of research — at least in terms of the liver” said David Brenner, MD, Vice Chancellor for Health Sciences, dean of the UC San Diego School of Medicine and co-author of the paper. “The old evidence and assumptions about the source of fibroblasts and the role of FSP1 as a marker are not valid.”
Specifically, in experiments using cell cultures, human liver samples and mouse models, the researchers found no evidence of EMT — that transformed epithelial cells became liver fibroblasts. Rather, endogenous stellate cells appear to be the culprit, though the scientists note many types of cells seem to contribute, directly or indirectly, to liver fibrosis.
Likewise, experiments proved FSP1 to be an unreliable marker for fibrosis. Cells containing FSP1 increased in human and experimental liver disease and in liver cancer, but researchers found that liver fibroblasts do not express the protein, nor do hepatic stellate cells — a major cell type involved in liver fibrosis. Similarly, FSP1 was determined not to be a marker for myofibroblasts (a fibroblast with some properties of a smooth muscle cell) or any precursors of myofibroblasts.
“There have been hundreds of papers based on FSP1 as a marker,” said Brenner. “That thinking now seems to have been a mistake. One of the take-home messages of this paper is that FSP1 clearly can’t be reliably used as a marker.”
On the other hand, the scientists discovered that FSP1 is a consistent marker for a previously unknown subset of inflammatory white blood cells or macrophages found in injured livers. The protein appears to also perform biological functions in the macrophages, though these remain to be determined.
“It’s a whole new class of monocytes,” said Brenner. “We don’t know what they do, but they’re worth investigating.”
Co-authors of the study are Christoph H. Osterreicher of the Department of Medicine, Laboratory of Gene Regulation and Signal Transduction and Department of Pharmacology, all at UC San Diego, and of the Institute of Pharmacology, Center for Physiology and Pharmacology and the Department of Internal Medicine, Division of Gastroenterology at Medical University of Vienna in Austria; Melitta Penz-Osterreicher of the Department of Medicine at UC San Diego and the Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna; Sergei I. Grivennikov and Monica Guma of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, UC San Diego; Ekaterina K. Koltsova of the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology; Christian Datz of the Department of Internal Medicine, General Hospital Oberndorf in Austria; Roman Sasik and Gary Hardiman of Biomedical Genomics Microarray Facility, Department of Medicine, UC San Diego; and Michael Karin of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology at UC San Diego.
Source
Diagnosis of Early Hepatocellular Carcinoma: Ideal Goal, But Not Yet There
Gastroenterology
Volume 140, Issue 1 , Pages 358-360, January 2011
Silvia Tremosini, Jordi Bruix
published online 17 November 2010
Sangiovanni A, Manini MA, Iavarone M, et al. (1st Division of Gastroenterology, Fondazione IRCCS CÃ Granda Ospedale Maggiore Policlinico, Milan, Italy). The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638–644.
The study by Sangiovanni et al prospectively evaluates the sensitivity, specificity and diagnostic accuracy of contrast-enhanced ultrasound (CEUS), computed tomography (CT), and magnetic resonance (MRI) for the diagnosis of hepatocellular carcinoma (HCC) after detecting de novo liver nodules detected in patients with compensated cirrhosis undergoing surveillance with ultrasound (US). The gold standard for the diagnosis of HCC has been fine needle biopsy and the typical radiologic pattern for the radiologic diagnosis of HCC was hypervascularization in the arterial phase with portal/venous washout.
Sixty-four patients were enrolled in this study, with a total of 67 liver nodules detected under US. The size of the lesions ranged from 0.8 to 2.7 cm (mean, 1.6). All nodules were examined by CEUS-CT-MRI and fine needle biopsy. On histologic examination, 66% were HCC, 3% were intrahepatic cholangiocarcinomas, and 31% were macroregenative nodules or low dysplastic nodules. Biopsies were repeated in all undiagnosed cases; benign lesions underwent an enhanced radiologic follow-up. Nine nodules (26%) had the typical vascular pattern of HCC demonstrated by CE-US, 16 (47%) by CT, and 14 (44%) by MRI. None of the nodules histologically classified as non-HCC showed the typical vascular pattern of HCC. The sensitivity of the combination of 2 imaging techniques (CEUS+CT, CEUS+MRI, CT+MRI) was 21%, 18%, and 26%, respectively, and the specificity was 100%. The rates of positive findings with 2 concordant techniques were comparable in terms of sensitivity, specificity, and accuracy with 3 imaging techniques, in combination. In 1- to 2-cm nodules, the typical radiologic vascular pattern for HCC was more often obtained by CT and MRI alone than CEUS+MRI (P = .027 and P = .031, respectively) or CEUS+CT (P = .038 and P = .043, respectively). CT and MRI had comparable sensitivities for the typical vascular pattern of HCC (44% and 44%), whereas CEUS had a lower sensitivity (26%). The typical vascular pattern of HCC was identified in 65% by a single technique, versus 35% by ≥2 techniques. This finding suggests that a confident diagnosis could be done by a single imaging technique showing the typical vascular pattern. This would significantly reduce the need for fine needle biopsy investigations, without modifying the costs calculated on the basis of the Italian National Health System.
Comment
HCC-related mortality can be reduced by prevention of the acquisition of risk factors (such as viral infection, excessive alcohol intake, or obesity) or by achieving its early detection with application of potentially curative treatment such as resection, liver transplantation, and ablation. In all instances, the smaller the HCC at diagnosis, the higher the likelihood of long-term success after therapy. Accordingly, the goal of screening programs in the population at risk (namely, patients with cirrhosis of any etiology) is to detect and treat HCC at an early stage and, specifically, when it has not grown >2 cm in diameter. Although tumor marker (alfa fetoprotein) determination is not useful for this purpose (Aliment Pharmacol Ther 2009;30:37–47), US is able to detect such small nodules. The critical point at that time is how to confirm diagnosis before treatment indication. Image-guided biopsy is known to have a relevant rate of false negatives and, in addition, is associated with risks of bleeding and potential malignant seeding. As a consequence, HCC diagnosis is frequently established by imaging criteria that may vary across centers. The EASL (J Hepatol 2001;35:421–430) and the American Association for the Study of Liver Diseases (AASLD) guidelines (Hepatology 2005;42:1208–1236) provided a set of definitions that would establish homogeneous definitions to be used for this purpose in patients with cirrhosis, whereas HCC diagnosis in patients without this condition would still require a positive biopsy. Radiologic diagnosis is based on the contrast enhancement pattern at dynamic imaging. Thereby, intense contrast uptake in the arterial phase followed by contrast washout in the venous/delayed phase is considered specific for HCC. In large tumors, imaging characterization is not a major difficulty requiring major expertise, but in nodules <2 cm, the recognition of the specific profile is more challenging. To avoid false-positive diagnoses because of equivocal findings, the AASLD 2005 guidelines allowed HCC >2 cm to be diagnosed with a single dynamic technique, whereas in HCC <2 cm, coincidental findings by 2 of them (CEUS, CT, MRI) were requested. Otherwise, a biopsy would be mandatory. Several studies have validated this diagnostic approach and allowed a refinement of the criteria. In a prospective study (Hepatology 2008;47:97–104) in nodules <2 cm, it was shown that the diagnostic strategy was correct, but that the need to have coincidental findings by 2 techniques significantly reduced the sensitivity of the criteria to around 33%. At the same time, it was shown that using MRI alone the sensitivity would be almost doubled and the specificity would still be almost 100%. In a separate study (Hepatology 2010;51:2010–2029), it was shown that CEUS may incur a false-positive HCC diagnosis in patients with intrahepatic cholangiocarcinoma, a malignancy that is also more frequently observed in patients with cirrhosis and has a completely different treatment strategy. Therefore, some cholangiocarcinomas exhibit the “arterial uptake followed by washout” profile that is ascribed to HCC; fortunately, MRI does not incur in such misdiagnosis (Hepatology 2009;50:791–798).
Finally, the study by Sangiovanni et al shows that the combination of techniques to establish diagnosis increases the economic burden of the clinical process (more imaging techniques and biopsies are needed before therapy), although the diagnostic accuracy that is gained is marginal. Similar findings have been generated in a similar study conducted in Canada (Hepatology 2008;48:362A) and as a whole all this dataset has provided the background to update the AASLD guidelines in 2010 (available from: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf). In them, the recommendation for HCC diagnosis allows a single imaging technique to be used among CT and MRI, and if it is nondiagnostic, the decision has to choose between the second technique or a biopsy is needed. MRI has been extensively validated but according to the specifics of the clinical care setting and profile of the patients, physicians will have to decide whether a negative result by the first of them to be used should prime the use of the second one, or if it is more effective to decide to take a biopsy with all its limitations and risks.
Having exposed the background for the novel strategy for HCC diagnosis, it is worth considering to which extent it will be feasible to establish diagnosis at the ideal size of <2 cm. The transition from low- to high-grade dysplasia and very early HCC usually occurs below this cutoff. Two types of HCC <2 cm can be distinguished: Early HCC and progressed HCC. Early HCC has a vaguely nodular appearance and is well differentiated. It corresponds to the very early HCC stage of the Barcelona Clinic Liver Cancer classification or the carcinoma in situ entity proposed by others (Hepatology 1998;28:1241–12469). Because of the absence of microvascular invasion and the lower proliferative profile, very early HCC has a longer time to recurrence and a higher 5-year survival rate compared with progressed HCC. This has a distinctly nodular pattern and is mostly moderately differentiated, often with evidence of microvascular invasion. On imaging, very early HCC has not yet developed the arterial network that translates into the imaging profile used for diagnosis. Indeed, in a recent study by the same Italian group (Hepatology 2010;52:1723–1730) it has been shown that small, well-differentiated HCC fail to present the imaging diagnostic pattern more frequently than in tumors that have a moderate-to-poor differentiation degree.
Taking into account these comments, it is clear that the target of screening programs that aim to provide long-term survival free of disease recurrence is to detect HCC at the very early stage, but diagnostic confirmation by MRI or CT will remain unmet in a large number of patients. Thus, the nodule will be detected by screening US, but no final imaging diagnosis will be feasible because the same appearance can correspond to a benign condition. Biopsy is to be requested, but again the diagnostic sensitivity is limited in very early HCC because it is composed of well-differentiated hepatocytes that do not easily allow the distinction from nonmalignant nodules. Even within expert pathologists, there is some degree of discrepancy after development of consensus criteria (Hepatology 2009;49:658–664). Immunostaining for different proteins such as Glypican 3, Heat Shock Protein 70, and Glutamyne Synthetase (J Hepatol 2009;50:746–754) may provide some reinforcement for HCC suspicion, but well-established criteria for unequivocal diagnosis need development and validation. Gene signatures have also been proposed to solve the difficulty (Gastroenterology 2006;131:1758–1767); however, validation is lacking. Ultimately, most proposals have been raised using surgical tissues, but in the clinical arena we have only the limited tissue sample obtained by biopsy; in tiny lesions, the puncture may not only sample the nodule, but also—or just—the surrounding tissue. Hopefully, new radiology techniques with organ-specific contrasts will help to overcome the current imitation and the same is expected in the field of tumor markers by the use of proteomics or metabolomics.
It should be stressed that these comments should not be seen as a disappointment or a pessimistic view, but rather the opposite. Some years ago, the usual concept was that HCC was impossible to be diagnosed at a curative stage and that the effort was useless. Now, we are struggling with very small nodules to increase the impact of the treatment options that we have. Facing challenges and framing the difficulties should be seen as the first step for their solution.
PII: S0016-5085(10)01616-1
doi:10.1053/j.gastro.2010.11.012
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 140, Issue 1 , Pages 358-360, January 2011
Silvia Tremosini, Jordi Bruix
published online 17 November 2010
Sangiovanni A, Manini MA, Iavarone M, et al. (1st Division of Gastroenterology, Fondazione IRCCS CÃ Granda Ospedale Maggiore Policlinico, Milan, Italy). The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638–644.
The study by Sangiovanni et al prospectively evaluates the sensitivity, specificity and diagnostic accuracy of contrast-enhanced ultrasound (CEUS), computed tomography (CT), and magnetic resonance (MRI) for the diagnosis of hepatocellular carcinoma (HCC) after detecting de novo liver nodules detected in patients with compensated cirrhosis undergoing surveillance with ultrasound (US). The gold standard for the diagnosis of HCC has been fine needle biopsy and the typical radiologic pattern for the radiologic diagnosis of HCC was hypervascularization in the arterial phase with portal/venous washout.
Sixty-four patients were enrolled in this study, with a total of 67 liver nodules detected under US. The size of the lesions ranged from 0.8 to 2.7 cm (mean, 1.6). All nodules were examined by CEUS-CT-MRI and fine needle biopsy. On histologic examination, 66% were HCC, 3% were intrahepatic cholangiocarcinomas, and 31% were macroregenative nodules or low dysplastic nodules. Biopsies were repeated in all undiagnosed cases; benign lesions underwent an enhanced radiologic follow-up. Nine nodules (26%) had the typical vascular pattern of HCC demonstrated by CE-US, 16 (47%) by CT, and 14 (44%) by MRI. None of the nodules histologically classified as non-HCC showed the typical vascular pattern of HCC. The sensitivity of the combination of 2 imaging techniques (CEUS+CT, CEUS+MRI, CT+MRI) was 21%, 18%, and 26%, respectively, and the specificity was 100%. The rates of positive findings with 2 concordant techniques were comparable in terms of sensitivity, specificity, and accuracy with 3 imaging techniques, in combination. In 1- to 2-cm nodules, the typical radiologic vascular pattern for HCC was more often obtained by CT and MRI alone than CEUS+MRI (P = .027 and P = .031, respectively) or CEUS+CT (P = .038 and P = .043, respectively). CT and MRI had comparable sensitivities for the typical vascular pattern of HCC (44% and 44%), whereas CEUS had a lower sensitivity (26%). The typical vascular pattern of HCC was identified in 65% by a single technique, versus 35% by ≥2 techniques. This finding suggests that a confident diagnosis could be done by a single imaging technique showing the typical vascular pattern. This would significantly reduce the need for fine needle biopsy investigations, without modifying the costs calculated on the basis of the Italian National Health System.
Comment
HCC-related mortality can be reduced by prevention of the acquisition of risk factors (such as viral infection, excessive alcohol intake, or obesity) or by achieving its early detection with application of potentially curative treatment such as resection, liver transplantation, and ablation. In all instances, the smaller the HCC at diagnosis, the higher the likelihood of long-term success after therapy. Accordingly, the goal of screening programs in the population at risk (namely, patients with cirrhosis of any etiology) is to detect and treat HCC at an early stage and, specifically, when it has not grown >2 cm in diameter. Although tumor marker (alfa fetoprotein) determination is not useful for this purpose (Aliment Pharmacol Ther 2009;30:37–47), US is able to detect such small nodules. The critical point at that time is how to confirm diagnosis before treatment indication. Image-guided biopsy is known to have a relevant rate of false negatives and, in addition, is associated with risks of bleeding and potential malignant seeding. As a consequence, HCC diagnosis is frequently established by imaging criteria that may vary across centers. The EASL (J Hepatol 2001;35:421–430) and the American Association for the Study of Liver Diseases (AASLD) guidelines (Hepatology 2005;42:1208–1236) provided a set of definitions that would establish homogeneous definitions to be used for this purpose in patients with cirrhosis, whereas HCC diagnosis in patients without this condition would still require a positive biopsy. Radiologic diagnosis is based on the contrast enhancement pattern at dynamic imaging. Thereby, intense contrast uptake in the arterial phase followed by contrast washout in the venous/delayed phase is considered specific for HCC. In large tumors, imaging characterization is not a major difficulty requiring major expertise, but in nodules <2 cm, the recognition of the specific profile is more challenging. To avoid false-positive diagnoses because of equivocal findings, the AASLD 2005 guidelines allowed HCC >2 cm to be diagnosed with a single dynamic technique, whereas in HCC <2 cm, coincidental findings by 2 of them (CEUS, CT, MRI) were requested. Otherwise, a biopsy would be mandatory. Several studies have validated this diagnostic approach and allowed a refinement of the criteria. In a prospective study (Hepatology 2008;47:97–104) in nodules <2 cm, it was shown that the diagnostic strategy was correct, but that the need to have coincidental findings by 2 techniques significantly reduced the sensitivity of the criteria to around 33%. At the same time, it was shown that using MRI alone the sensitivity would be almost doubled and the specificity would still be almost 100%. In a separate study (Hepatology 2010;51:2010–2029), it was shown that CEUS may incur a false-positive HCC diagnosis in patients with intrahepatic cholangiocarcinoma, a malignancy that is also more frequently observed in patients with cirrhosis and has a completely different treatment strategy. Therefore, some cholangiocarcinomas exhibit the “arterial uptake followed by washout” profile that is ascribed to HCC; fortunately, MRI does not incur in such misdiagnosis (Hepatology 2009;50:791–798).
Finally, the study by Sangiovanni et al shows that the combination of techniques to establish diagnosis increases the economic burden of the clinical process (more imaging techniques and biopsies are needed before therapy), although the diagnostic accuracy that is gained is marginal. Similar findings have been generated in a similar study conducted in Canada (Hepatology 2008;48:362A) and as a whole all this dataset has provided the background to update the AASLD guidelines in 2010 (available from: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf). In them, the recommendation for HCC diagnosis allows a single imaging technique to be used among CT and MRI, and if it is nondiagnostic, the decision has to choose between the second technique or a biopsy is needed. MRI has been extensively validated but according to the specifics of the clinical care setting and profile of the patients, physicians will have to decide whether a negative result by the first of them to be used should prime the use of the second one, or if it is more effective to decide to take a biopsy with all its limitations and risks.
Having exposed the background for the novel strategy for HCC diagnosis, it is worth considering to which extent it will be feasible to establish diagnosis at the ideal size of <2 cm. The transition from low- to high-grade dysplasia and very early HCC usually occurs below this cutoff. Two types of HCC <2 cm can be distinguished: Early HCC and progressed HCC. Early HCC has a vaguely nodular appearance and is well differentiated. It corresponds to the very early HCC stage of the Barcelona Clinic Liver Cancer classification or the carcinoma in situ entity proposed by others (Hepatology 1998;28:1241–12469). Because of the absence of microvascular invasion and the lower proliferative profile, very early HCC has a longer time to recurrence and a higher 5-year survival rate compared with progressed HCC. This has a distinctly nodular pattern and is mostly moderately differentiated, often with evidence of microvascular invasion. On imaging, very early HCC has not yet developed the arterial network that translates into the imaging profile used for diagnosis. Indeed, in a recent study by the same Italian group (Hepatology 2010;52:1723–1730) it has been shown that small, well-differentiated HCC fail to present the imaging diagnostic pattern more frequently than in tumors that have a moderate-to-poor differentiation degree.
Taking into account these comments, it is clear that the target of screening programs that aim to provide long-term survival free of disease recurrence is to detect HCC at the very early stage, but diagnostic confirmation by MRI or CT will remain unmet in a large number of patients. Thus, the nodule will be detected by screening US, but no final imaging diagnosis will be feasible because the same appearance can correspond to a benign condition. Biopsy is to be requested, but again the diagnostic sensitivity is limited in very early HCC because it is composed of well-differentiated hepatocytes that do not easily allow the distinction from nonmalignant nodules. Even within expert pathologists, there is some degree of discrepancy after development of consensus criteria (Hepatology 2009;49:658–664). Immunostaining for different proteins such as Glypican 3, Heat Shock Protein 70, and Glutamyne Synthetase (J Hepatol 2009;50:746–754) may provide some reinforcement for HCC suspicion, but well-established criteria for unequivocal diagnosis need development and validation. Gene signatures have also been proposed to solve the difficulty (Gastroenterology 2006;131:1758–1767); however, validation is lacking. Ultimately, most proposals have been raised using surgical tissues, but in the clinical arena we have only the limited tissue sample obtained by biopsy; in tiny lesions, the puncture may not only sample the nodule, but also—or just—the surrounding tissue. Hopefully, new radiology techniques with organ-specific contrasts will help to overcome the current imitation and the same is expected in the field of tumor markers by the use of proteomics or metabolomics.
It should be stressed that these comments should not be seen as a disappointment or a pessimistic view, but rather the opposite. Some years ago, the usual concept was that HCC was impossible to be diagnosed at a curative stage and that the effort was useless. Now, we are struggling with very small nodules to increase the impact of the treatment options that we have. Facing challenges and framing the difficulties should be seen as the first step for their solution.
PII: S0016-5085(10)01616-1
doi:10.1053/j.gastro.2010.11.012
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Statin Therapy Improves Sustained Virologic Response Among Diabetic Patients With Chronic Hepatitis
Gastroenterology
Volume 140, Issue 1 , Pages 144-152.e2, January 2011
CGowtham A. Rao, Prashant K. Pandya
Received 24 February 2010; accepted 24 August 2010. published online 13 September 2010.
Abstract
Background & Aims
Patients with chronic hepatitis C infection are 2- to 3-fold more likely to develop type 2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of a national Veterans Affairs administrative database.
Methods
We analyzed data from the Veterans Affairs Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetic patients (n = 1704) and nondiabetic patients (n = 6589). Significant predictors of SVR were identified by logistic regression analysis.
Results
Diabetic patients had a lower SVR compared with nondiabetic patients (21% vs 27%, respectively, P < .001). Diabetic patients had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetic patients for SVR, the positive predictors were higher low-density lipoprotein (odds ratio [OR], 1.45; P = .0129), use of statin (OR, 1.52; P = .0124), and lower baseline viral load (OR, 2.31; P < .001), whereas insulin therapy (OR, 0.7; P = .0278) was a negative predictor. Diabetic patients on statins had higher pretreatment viral loads (log 6.2 vs 6.4, respectively, P = .006) but better early virologic response. There was a graded inverse relationship between Hemoglobin A1c and SVR rate (P = .0482). This relationship was significant among insulin users (P = .0154) and non-significant among metformin users (P = .5853).
Conclusions
Statin use was associated with an improved SVR among both diabetic patients and nondiabetic patients receiving combination antiviral therapy. Diabetic patients who received insulin achieved lower SVR compared with those not receiving insulin. Poor diabetes control was associated with lower SVR rates.
Keywords: Hepatitis C, Diabetes, Veterans, Statins, Metformin, Insulin
Source
Volume 140, Issue 1 , Pages 144-152.e2, January 2011
CGowtham A. Rao, Prashant K. Pandya
Received 24 February 2010; accepted 24 August 2010. published online 13 September 2010.
Abstract
Background & Aims
Patients with chronic hepatitis C infection are 2- to 3-fold more likely to develop type 2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of a national Veterans Affairs administrative database.
Methods
We analyzed data from the Veterans Affairs Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetic patients (n = 1704) and nondiabetic patients (n = 6589). Significant predictors of SVR were identified by logistic regression analysis.
Results
Diabetic patients had a lower SVR compared with nondiabetic patients (21% vs 27%, respectively, P < .001). Diabetic patients had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetic patients for SVR, the positive predictors were higher low-density lipoprotein (odds ratio [OR], 1.45; P = .0129), use of statin (OR, 1.52; P = .0124), and lower baseline viral load (OR, 2.31; P < .001), whereas insulin therapy (OR, 0.7; P = .0278) was a negative predictor. Diabetic patients on statins had higher pretreatment viral loads (log 6.2 vs 6.4, respectively, P = .006) but better early virologic response. There was a graded inverse relationship between Hemoglobin A1c and SVR rate (P = .0482). This relationship was significant among insulin users (P = .0154) and non-significant among metformin users (P = .5853).
Conclusions
Statin use was associated with an improved SVR among both diabetic patients and nondiabetic patients receiving combination antiviral therapy. Diabetic patients who received insulin achieved lower SVR compared with those not receiving insulin. Poor diabetes control was associated with lower SVR rates.
Keywords: Hepatitis C, Diabetes, Veterans, Statins, Metformin, Insulin
Source
Clinical Trials Report Final Results on New Treatments for Hepatitis C Virus
Gastroenterology
Volume 140, Issue 1 , Page 6, January 2011
Les Lang
published online 15 November 2010.
Richard Peek and K. Rajender Reddy, Section Editors
Results of clinical trials of 2 new treatments for hepatitis C (HCV) that enhance sustained viral response (SVR) rates were presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases in Boston, Massachusetts, October 29–November 2, 2010.
SVR have been <50% in HCV G1 patients, especially in black Americans. The SPRINT-2 study assessed the safety and efficacy of Boceprevir (BOC), a HCV-NS3 protease inhibitor, when combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with HCV genotype (G) 1. This Phase III, international, double-blind, randomized study compared a 4-week lead-in (LI) treatment period with P/R, followed by (1) P/R plus placebo for 44 weeks (48P/R); (2) response-guided therapy (RGT): BOC plus P/R for 24 weeks, with an additional 20 weeks of P/R only if detectable HCV RNA during weeks 8–24 (LI+24 BOC/P/R*20 P/R); or (3) BOC plus P/R for 44 weeks (LI+44 BOC/P/R). The primary efficacy end point was SVR 24 weeks post-therapy in all randomized patients treated with any study medication. Non-black (cohort 1) and black (cohort 2) patients were enrolled and analyzed separately per protocol. Final results showed that BOC/P/R significantly increased SVR in both the RGT and 48-week treatment arms over standard of care by ∼70%. BOC was well tolerated; although reported more often in BOC recipients, anemia rarely led to treatment discontinuation. Compared with 44 weeks of triple therapy after the LI period, RGT with LI+24BOC/P/R*20P/R produced comparable SVR.
Also presented at American Association for the Study of Liver Diseases were final results of the Phase III ADVANCE Study, a 3-arm double-blind, randomized, placebo-controlled trial assessing efficacy and safety of 2 telaprevir (TVR, T)-based, response-guided regimens that were compared with peginterferon alfa-2a 180 μg per week and ribavirin 1000–1200 mg/d (PR) in treatment-naïve patients with chronic HCV G1 infection. The researchers report that a significantly greater proportion of patients achieved SVR with 12- and 8-week telaprevir-based combination regimens (75% and 69%, respectively). This was compared with the PR, 48 weeks control arm (44%; P < .0001). The safety and tolerability profile of telapervir in this trial was consistent with the profile previously reported. There also was improvement in treatment discontinuation rates owing to adverse events, including rash and anemia.
Another treatment trial called the ILLUMINATE study also evaluated telaprevir therapy along with pegylated interferon and ribavirin and demonstrated that the paradigm of RGT, as noted in the SPRINT-2 and ADVANCE studies as well, is very likely to become the standard of care as the treatment duration can be truncated in the majority of patients, while not compromising rates of SVR.
PII: S0016-5085(10)01635-5
doi:10.1053/j.gastro.2010.11.031
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 140, Issue 1 , Page 6, January 2011
Les Lang
published online 15 November 2010.
Richard Peek and K. Rajender Reddy, Section Editors
Results of clinical trials of 2 new treatments for hepatitis C (HCV) that enhance sustained viral response (SVR) rates were presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases in Boston, Massachusetts, October 29–November 2, 2010.
SVR have been <50% in HCV G1 patients, especially in black Americans. The SPRINT-2 study assessed the safety and efficacy of Boceprevir (BOC), a HCV-NS3 protease inhibitor, when combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with HCV genotype (G) 1. This Phase III, international, double-blind, randomized study compared a 4-week lead-in (LI) treatment period with P/R, followed by (1) P/R plus placebo for 44 weeks (48P/R); (2) response-guided therapy (RGT): BOC plus P/R for 24 weeks, with an additional 20 weeks of P/R only if detectable HCV RNA during weeks 8–24 (LI+24 BOC/P/R*20 P/R); or (3) BOC plus P/R for 44 weeks (LI+44 BOC/P/R). The primary efficacy end point was SVR 24 weeks post-therapy in all randomized patients treated with any study medication. Non-black (cohort 1) and black (cohort 2) patients were enrolled and analyzed separately per protocol. Final results showed that BOC/P/R significantly increased SVR in both the RGT and 48-week treatment arms over standard of care by ∼70%. BOC was well tolerated; although reported more often in BOC recipients, anemia rarely led to treatment discontinuation. Compared with 44 weeks of triple therapy after the LI period, RGT with LI+24BOC/P/R*20P/R produced comparable SVR.
Also presented at American Association for the Study of Liver Diseases were final results of the Phase III ADVANCE Study, a 3-arm double-blind, randomized, placebo-controlled trial assessing efficacy and safety of 2 telaprevir (TVR, T)-based, response-guided regimens that were compared with peginterferon alfa-2a 180 μg per week and ribavirin 1000–1200 mg/d (PR) in treatment-naïve patients with chronic HCV G1 infection. The researchers report that a significantly greater proportion of patients achieved SVR with 12- and 8-week telaprevir-based combination regimens (75% and 69%, respectively). This was compared with the PR, 48 weeks control arm (44%; P < .0001). The safety and tolerability profile of telapervir in this trial was consistent with the profile previously reported. There also was improvement in treatment discontinuation rates owing to adverse events, including rash and anemia.
Another treatment trial called the ILLUMINATE study also evaluated telaprevir therapy along with pegylated interferon and ribavirin and demonstrated that the paradigm of RGT, as noted in the SPRINT-2 and ADVANCE studies as well, is very likely to become the standard of care as the treatment duration can be truncated in the majority of patients, while not compromising rates of SVR.
PII: S0016-5085(10)01635-5
doi:10.1053/j.gastro.2010.11.031
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
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