Showing posts with label disease progression. Show all posts
Showing posts with label disease progression. Show all posts

Friday, May 11, 2018

Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications

As a side note, according to the HCV treatment guidelines published by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America and the International Antiviral Society, the only contraindication to current chronic HCV treatment is in a patient with a short life expectancy that cannot be lengthened with treatment, with liver transplant, or with any other treatments. Overtime we have learned that treating people with lower-stage fibrosis increases SVR rates, and for persons who inject drugs, adherence and efficacy rates are comparable to those of patients who do not use injected drugs. In other words, treat all.

Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications
Page Axley, Sandhya Mudumbi, Shabnam Sarker, Yong-Fang Kuo, Ashwani Singal
Published: May 10, 2018


Background and aims
Advanced liver fibrosis is an important predictor of liver disease progression and mortality, and current guidelines recommend screening for complications of cirrhosis once patients develop F3 fibrosis. Our study compared liver disease progression and survival in patients with stage 3 (F3) and stage 4 (F4) fibrosis on liver biopsy.

Retrospective study of patients with F3 or F4 on liver biopsy followed for development of liver disease complications (variceal bleeding, ascites, and hepatic encephalopathy); hepatocellular carcinoma, and survival (overall and transplant free survival).

Of 2488 patients receiving liver biopsy between 01/02 and 12/12, a total of 294 (171 F3) were analyzed. Over a median follow up period of 3 years, patients with F4 (mean age 53 years, 63% male) compared to F3 (mean age 49 years, 43% male) had higher five year cumulative probability of any decompensation (38% vs. 14%, p<0.0001), including variceal bleed (10% vs. 4%, p = 0.014), ascites (21% vs. 9%, p = 0.0014), and hepatic encephalopathy (14% vs. 5%, p = 0.003). F4 patients also had lower overall 5-year survival (80% vs. 93%, p = 0.003) and transplant free survival (80% vs. 93%, p = 0.002). Probability of hepatocellular carcinoma in 5 years after biopsy was similar between F3 and F4 (1.2% vs. 2%, p = 0.54).

Compared to F4 stage, patients with F3 fibrosis have decreased risk for development of liver disease complications and better survival. Prospective well designed studies are suggested with large sample size and overcoming the limitations identified in this study, to confirm and validate these findings, as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.

Discussion Only
View full text article @ PLOS ONE

The main findings of our study are that patients with F4 fibrosis compared to those with F3 stage have a) higher probability of developing decompensation of liver disease including ascites, variceal bleeding, and hepatic encephalopathy and b) lower overall and transplant-free survival.

In patients with chronic HCV infection, several previous studies have reported increased rate of liver disease complications related to advanced fibrosis stage. In a study of 1050 HCV patients, 57% with Ishak stage 4 to 6, there was cumulative incidence of first liver-disease complication of 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6 in the 6 year follow up period.[8] The probability of liver disease complication, death, or liver transplant increased with successive fibrosis stages. Stages 4 and 5 of the Ishak system represent advanced bridging fibrosis and/or early nodule formation and have shown excellent correlation with F3 in the METAVIR system.[9]

Another study based on four large US-integrated health systems retrospectively examined 917 chronic HCV patients with F3 and F4 fibrosis for 5 years after liver biopsy.[10] For liver disease related complications comparing F4 vs. F3 fibrosis, there was increased risk for ascites (14 vs. 7.1%), esophageal varices with bleeding (4.4 vs. 1.2%), and hepatic encephalopathy (3.9 vs. 1.4%) in the 5 year observation period after liver biopsy. The 5-year survival was 77% in F4 fibrosis compared to 91% in F3 fibrosis. The 5-year probability for HCC development was 3.1% in F3 fibrosis and 8.8% in F4 fibrosis.

Huang et al. evaluated 153 patients with F3 fibrosis (mean age 45, 54% male) and F4 fibrosis (mean age 51, 54% male) over a mean follow up period of 9 years and found that F4 had significantly higher risk of liver-related complications, hepatocellular carcinoma, and death than F3 (p < 0.001).[11] Very similar to our findings, the 5-year survival in patients with F4 fibrosis was 83% compared to 96% in patients with F3 fibrosis. The 5-year probability for development of HCC patients with F3 fibrosis was 0% compared to 6% in F4 patients. At year 7, probabilities for HCC development jumped to 16% in patients with F4 fibrosis and increased to 2% in patients with F3 fibrosis. Unlike these previous 2 studies described, our study failed to show a difference in the risk for development of HCC in F3 compared to F4 fibrosis, likely because of the shorter follow up period of only 5 years and the inclusion of non-HCV patients who have lower risk for HCC development.

In NAFLD, advanced fibrosis has also been identified as leading to higher rates of liver-disease related complications and mortality.[12, 13] In a recent study of 646 patients (mean age 48, 62% male) with well-defined NAFLD followed for a mean of 20 years, patients with F4 fibrosis had a 3-fold increase in liver disease related complications and a 2-fold increase in overall mortality compared to those with F3 fibrosis.[14] The average time for patients with F3 fibrosis to develop severe liver disease as defined by the ICD-code diagnosis of cirrhosis, liver failure, HCC, or decompensated liver disease was 6 years (95% CI 2.3–9.6), however the study did not differentiate between these outcomes or provide data on HCC incidence. In another large multi-center cohort study of 619 NAFLD patients (11.5% with stage 3 or 4 fibrosis) followed for a median of 12.6 years, F4 patients compared to F3 patients had a four-fold increased probability for liver disease related complications overall and two-fold increased risk of liver-related mortality.[13] Only 3 patients in the study developed HCC, and fibrosis stage for these patients was not reported.

To our knowledge, this is the first study showing that patients with F3 compared to F4 fibrosis have lower frequency of and longer time to development of liver disease complications irrespective of liver disease etiology. Our large cohort is also well characterized with liver fibrosis stage confirmed by two separate pathologists. Further, studies have shown good inter- and intraobserver reproducibility on the fibrosis staging using any classification including the Metavir fibrosis staging system.[5] Also, potential confounders of alcohol use and HCV treatment were equally distributed in the two groups ruling out to a great extent their impact on the outcomes. However, apart from inherent limitations of a retrospective study design, our study does suffer from potential selection bias as not everyone presenting for liver disease evaluation at our center underwent a liver biopsy examination. Further, our study excluded patients with F2 fibrosis, which could be used as a control group and compare with F3 fibrosis on development of outcomes. Although for analysis on decompensation and liver disease complications, we only analyzed patients developing the respective event after 30 days from liver biopsy, it is possible that some of the F3 patients may have transitioned to F4 on follow up, and it is difficult to ascertain the stage of fibrosis at which the decompensation occurred. Repeat liver biopsy or non-invasive imaging with transient elastography was not performed and limits us from identifying the patients that may have progressed from F3 to F4 fibrosis stage.

Regardless of underlying liver disease etiology, advanced hepatic fibrosis portends increased liver-associated complications and mortality.[1013, 1521] However, physicians need to be vigilant as these patients unpredictably may transition to F4 stage. In this regard, data are needed on the use of non-invasive serum and radiological markers including fibroscan and transient elastography, as basis for cost-effective management of these patients in clinical practice.

In summary, our study shows lower rate of and slower development of decompensation and liver disease complications, with better overall and transplant free survival among patients with biopsy conformed bridging or advanced fibrosis (F3) as compared to patients with cirrhosis (F4) irrespective of liver disease etiology. We suggest larger multicenter prospective studies overcoming the limitations identified in this study, to confirm and validate these findings as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.

Thursday, March 1, 2018

Impact of proton pump inhibitors on progression of liver disease in noncirrhotic hepatitis C infection

Proton Pump Inhibitors Are Associated With Accelerated Development of Cirrhosis, Hepatic Decompensation and Hepatocellular Carcinoma in Noncirrhotic Patients With Chronic Hepatitis C Infection

Results From ERCHIVES
D. K. Li; P. Yan; A-B. Abou-Samra; R. T. Chung; A. A. Butt 

This study assessed the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus infection. Are PPIs safe to use in these patients?

Full text available at Medscape, February 27, 2018. 

Note: Proton pump inhibitors (PPIs) are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). Treat a duodenal or stomach ulcer. Treat damage to the lower esophagus caused by acid reflux.

Aliment Pharmacol Ther. 2018;47(2):246-258.

Abstract and Introduction
Background Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear.

Aim To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection.

Methods Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use.

Results Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]).

Conclusions In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma.

Wednesday, November 22, 2017

HCV Advocate – Direct-Acting Antiviral Treatment & Decrease a Incidence of Liver Cancer

In Case You Missed It

SnapShots – Direct-Acting Antiviral Treatment & Decrease a Incidence of Liver Cancer
Alan Franciscus

Did you know that people who were treated with direct-acting antiviral (DAA) medications….
  • Were significantly less likely to die than the people who were untreated.
  • Had at least a 20% decrease in liver fibrosis after 24-weeks of the completion of DAA therapy
  • Experienced a 71% reduction in liver cancer risk after being cured with a DAA medication.
 The studies on this blog looked at treatment with DAAs to find out if curing hepatitis C (HCV) with DAAs improved HCV disease progression and reduced the risk of liver cancer.

Continue reading........

Sunday, September 3, 2017

Hepatitis C patients in the US and China, and factors influencing disease stage

The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease
Rao, E. Wu, S. Fu, M. Yang, B. Feng, A. Lin, R. Fei, R. J. Fontana, A. S. Lok, L. Wei First

Published: 22 August 2017
Full publication history DOI: 10.1111/apt.14273

In summary, our study found a higher per cent of US patients with chronic HCV infection had cirrhosis or HCC compared to Chinese patients even among patients with similar estimated duration of infection. We believe that a higher prevalence of concomitant fatty liver in the US patients may be a major contributor to this observed difference. Our findings if confirmed highlight that management of glycometabolic abnormalities should go hand in hand with anti-viral treatment for patients with chronic hepatitis C and concomitant obesity or diabetes.

View full text journal article online

Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China.

To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage.

Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria.

One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis.

HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.

Monday, October 5, 2015

Hepatitis C Untreated- NYU Researchers Find Serious Liver Damage in Mid- to Late-Adulthood Among People Who Inject Drugs

NYU Researchers Find Development of Serious Liver Damage in Mid- to Late-Adulthood Among People Who Inject Drugs Untreated With Hepatitis C

October 5, 2015

Few people who inject drugs are engaged in needed care for chronic HCV infection; Early engagement in treatment needs to be a policy priority for these individuals

The Hepatitis C virus (HCV) infection is a chronic blood-borne viral infection that affects an estimated 160 million people, or 2-3% of the population world-wide. Alarmingly, chronic HCV infection accounts for one-quarter of the cases of cirrhosis and hepatocellular carcinoma (HCC). If HCV is left untreated, chronic liver disease will occur in 60–70% of the cases, cirrhosis in 5–20% of the cases, and 1–5% will die from decompensated cirrhosis or HCC.

In most high-income countries, such as the United States, where drug injection is the primary route of HCV transmission, the disease is concentrated among people who inject drugs (PWID). While it is estimated that 50–80% of PWID are chronically infected, fewer than 5% of PWID have received treatment.

In a new study, “Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis,” published in the International Journal of Drug Policy, a team of researchers from New York University’s Center for Drug Use and HIV Research (CDUHR) assessed existing data on the natural history of HCV among PWID. A total of twenty-one studies examined over 8500 PWID, who contributed nearly 120,000 person-years at risk, for the study of four major HCV-related outcomes included in the synthesis.

“Understanding HCV disease progression rates among people who inject drugs (PWID) is important to setting policy to expand access to detection, diagnosis and treatment, and in forecasting the burden of disease,” said Holly Hagan, PhD, the principal investigator for the HCV Synthesis Project, who also is a professor at New York University College of Nursing (NYUCN) and co-director at CDUHR. “In this study we synthesized existing data on the natural history of HCV among PWID, including fibrosis progression rates and the incidence of compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma.”

Among the PWID, the mean age they acquired HCV was 21 years, and the mean duration of infection was 14 years. “Based on our analysis of fibrosis progression, PWID, on average, will have moderate liver fibrosis between 26–38 years after HCV infection and will develop cirrhosis within 34–46 years,” said Dr. Hagan. “In the course of the disease progression, cirrhosis may lead to HCC, the prognosis for which is extremely poor—the median length of survival is approximately 12–15 months. Since PWID tend to be infected at an early age, they are likely to develop HCC in mid- to late-adulthood, resulting in losses of individuals in their most productive period of life.”

Given their findings, the researchers note the health-related benefits of early engagement, especially since the new HCV treatments feature shorter drug regimens that are very likely to result in cure. However, such options are expensive and their eligibility guidelines may explicitly exclude active drug users. Furthermore, many public insurance programs in the United States, such as Medicaid, have restricted coverage of these new treatments to those in the more advanced stages of the disease.

“These limitations may delay treatment for years and, thus, will disproportionately affect PWID and other low-income patients,” said Dr. Hagan. “These restrictions also are in conflict with new HCV treatment guidelines from the American Association for the Study of Liver Disease (2015), which explicitly state that active injection drug users should be prioritized for treatment in part because of the risk of transmission to susceptible injection partners.”

Dr. Hagan and the team of NYU researchers hope that by providing a better understanding of HCV progression rates among PWID, they can help inform policy to expand access to detection, diagnosis, and treatment. However, Dr. Hagan emphasized that there is a clear need for further study into the impact of alcohol consumption and other factors on disease development in PWID, as there are few studies that consistently report this information. Dr. Hagan added: “Unfortunately, the restrictions on HCV treatment force us to identify other ways to slow disease progression.”

Researcher Affiliations: Daniel J. Smith a; Joan Combellick a; Ashly E. Jordan a,b; Holly Hagan a,b.

a. College of Nursing, New York University, NY, NY, USA

b. Center for Drug Use and HIV Research, New York University, NY, NY, USA

Acknowledgements: The authors of this study gratefully acknowledge Dr. Jason Fletcher for his statistical assistance. This study was supported by the National Institutes of Health, grant numbers 1R01DA034637 and P30DA011041.

Monday, June 1, 2015

What are the co-factors that increase severity of HCV disease and how should they be managed?

MedPage Today invited specialists from leading medical institutions to weigh in on the latest advancements in hepatitis C with one question each day for 10 days. In this installment, we asked: "What are the co-factors that increase severity of HCV disease and how should they be managed?"

Watch Video Here

Our participants are:
Andrew H. Talal, MD, professor of medicine, University at Buffalo
Andrew J. Muir, MD, associate professor of medicine, Duke University
Gregory T. Everson, MD, professor of medicine, University of Colorado

Thursday, November 13, 2014

Well-Controlled Hepatitis C No Dent on Lifespan

Medscape Medical News

Well-Controlled Hepatitis C No Dent on Lifespan

Laurie Barclay, MD
November 12, 2014

Survival in patients with chronic hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis who achieved sustained virological response (SVR) is similar to that of the general population, according to a retrospective study published in the November 12 issue of JAMA. However, patients who did not achieve SVR had lower life expectancy than their peers.

"Among patients with chronic HCV infection and bridging fibrosis or cirrhosis, attaining SVR was associated with survival comparable with that of the general population, whereas not attaining SVR was associated with reduced survival," write Adriaan J. van der Meer, MD, PhD, from the Erasmus MC University Medical Center Rotterdam, the Netherlands, and colleagues.

Previous studies have shown that patients with chronic HCV infection have a reduced lifespan compared with the general population. However, patients with chronic HCV infection and advanced hepatic fibrosis and SVR have a lower all-cause mortality than patients without SVR. What has not been clear until now is whether those patients with SVR have a shorter life expectancy than the general population.

Therefore, the investigators used data from a previous study to compare overall survival in patients with chronic HCV infection with and without SVR with that in the general population in the Netherlands, matched for age-, sex-, and calendar time-specific death rates. The sample consisted of 530 consecutive patients with chronic HCV monoinfection and biopsy-proven advanced hepatic fibrosis (Ishak fibrosis scores of 4, 5, or 6) who began interferon-based antiviral treatment between 1990 and 2003 at one of five large hepatology units in Europe and Canada.

At 24 weeks after patients stopped antiviral therapy, they underwent testing for SVR, defined as blood sample being negative for HCV RNA. Median duration of follow-up was 8.4 years, median age was 48 years, and 70% were male.

Of 454 patients (86%) with complete follow-up, 192 achieved SVR, 13 of whom died. Cumulative 10-year overall survival in patients who achieved SVR was 91.1%, which did not differ significantly from that in the age- and sex-matched general population.

Among patients who did not achieve SVR, there were 100 deaths, yielding a cumulative 10-year survival of 74.0%, which was significantly lower than that in the age- and sex-matched general population (P < .001).

Limitations of this study include its retrospective design, restriction to general population data available only for the Netherlands, and receipt of interferon-based therapy by all patients, limiting generalizability to those with other treatment regimens.

"The excellent survival among patients with advanced liver disease and SVR might be explained by the associations between SVR and regression of hepatic inflammation and fibrosis, reduced hepatic venous pressure gradient, reduced occurrence of hepatocellular carcinoma and liver failure, as well as reduced occurrence of diabetes mellitus, end-stage renal disease, and cardiovascular events," the study authors write. "Even though patients with cirrhosis and SVR remain at risk for hepatocellular carcinoma, the annual hepatocellular carcinoma incidence is low and survival is substantially better compared with those without SVR. Competing risks could also contribute."

The Foundation for Liver and Gastrointestinal Research in Rotterdam, the Netherlands, funded this study. Some of the study authors reported various financial disclosures involving Merck Sharp & Dohme, Gilead, Roche, Abbott, Novartis, Bristol-Myers Squibb, Hoffmann-LaRoche, Tibotec, Vertex, Clinical Care Options, Bayer, Novartis, Transgene, Achillion, AstraZeneca, Boehringer Ingelheim, Santaris, Janssen, Idenix, Presidio, Anadys, and/or Medtronic.

JAMA. 2014;32:1927-1928. Abstract

Thursday, November 6, 2014

Identifying Patients With Chronic Hepatitis C in Need of Early Treatment and Intensive Monitoring

Alimentary Pharmacology & Therapeutics
Systematic Review

Identifying Patients With Chronic Hepatitis C in Need of Early Treatment and Intensive
Monitoring Predictors and Predictive Models of Disease Progression

M. A. Konerman, S. Yapali, A. S. Lok

Aliment Pharmacol Ther. 2014;40(8):863-879.

Background Advances in hepatitis C therapies have led to increasing numbers of patients seeking treatment. As a result, logistical and financial concerns regarding how treatment can be provided to all patients with chronic hepatitis C (CHC) have emerged.
Aim To evaluate predictors and predictive models of histological progression and clinical outcomes for patients with CHC.
Methods MEDLINE via PubMed, EMBASE, Web of Science and Scopus were searched for studies published between January 2003 and June 2014. Two authors independently reviewed articles to select eligible studies and performed data abstraction.
Results Twenty-nine studies representing 5817 patients from 20 unique cohorts were included. The outcome incidence rates were widely variable: 16–61% during median follow-up of 2.5–10 years for fibrosis progression; 13–40% over 2.3–14.4 years for hepatic decompensation and 8–47% over 3.9–14.4 years for overall mortality. Multivariate analyses showed that baseline steatosis and baseline fibrosis score were the most consistent predictors of fibrosis progression (significant in 6/21 and 5/21, studies, respectively) while baseline platelet count (significant in 6/13 studies), aspartate and alanine aminotransferase (AST/ALT) ratio, albumin, bilirubin and age (each significant in 4/13 studies) were the most consistent predictors of clinical outcomes. Five studies developed predictive models but none were externally validated.
Conclusions Our review identified the variables that most consistently predict outcomes of patients with chronic hepatitis C allowing the application of risk based approaches to identify patients in need of early treatment and intensive monitoring. This approach maximises effective use of resources and costly new direct-acting anti-viral agents.


With the introduction of more efficacious and less toxic drugs, treatment of chronic hepatitis C (CHC) is evolving at a rapid pace. The two new direct-acting anti-viral agents (DAA), simeprevir and sofosbuvir, increase rates of sustained virological response (SVR) with shorter treatment durations compared to prior therapies.[1,2] Along with advances in therapy, there has been a focus on the public health impact of CHC. The Centers for Disease Control and Prevention, the Institute of Medicine, and the United States Preventive Services Task Force, have prioritised hepatitis C awareness, screening and diagnosis.[3–5] Treatment is also being advocated as a means to prevent hepatitis C virus (HCV) infection. As a result of these processes, the pool of potential treatment candidates is expected to balloon. This has caused the conundrum in HCV treatment to shift from 'Can we improve the efficacy and tolerability of HCV treatment?' to 'Can we afford to treat all patients with CHC?'

At the core of the dilemma is the high cost of these new drugs. The estimated wholesale price of a 12-week course of sofosbuvir in the United States (US) is $84 000 and of simeprevir $66 000.[6,7] These staggering costs exclude retail markup, and associated cost of pegylated interferon (IFN), ribavirin, physician visits and laboratory tests. While these new treatment regimens have SVR rates of 80–90%, and SVR has been shown to decrease cirrhosis complications, hepatocellular carcinoma (HCC) and liver-related mortality, even resource-replete countries like the US cannot afford to treat all those who are infected.[1,2,8] The logistical and financial barriers are much higher in resource-limited countries, many of which have higher prevalence of HCV infection than western countries. Clinicians and health policy makers will need to determine an optimal yet practical approach to provide these highly efficacious, but extremely costly therapies to this burgeoning patient population.

One solution is to adopt a risk-stratified approach that targets therapy to those at the greatest risk of disease progression. There have been many studies investigating risk factors for disease progression in patients with CHC but few have employed a longitudinal study design in generalisable patient populations using data that are routinely available in clinical practice. Results of the existing studies have also not been systematically summarised in a single document. Therefore, we performed a systematic review of the literature to (i) identify factors predictive of disease progression (fibrosis progression and clinical outcomes) in patients with CHC and (ii) assess existing predictive models.

Data Sources and Search Strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations in conducting this systematic review.[9] With the assistance of a medical research librarian, we performed serial literature searches for English and non-English articles. MEDLINE (via PubMed), EMBASE, Web of Science and Scopus were searched using the following keywords: 'cirrhosis' or 'liver cirrhosis' or 'fibrosis', 'hepatitis C' or 'hepatitis C, chronic' or 'chronic hepatitis C', 'disease progression' or 'progression' or 'decompensation'. Boolean operators and medical subject heading terms as well as other controlled vocabulary were used to enhance electronic searches. An example of specific search strategy details is shown in Table S1

All human subject studies published in full-text or abstract were eligible for inclusion. The search was limited to publications from 2003 to 2014 as this 10-year period contained the most contemporary and relevant data with respect to treatment and current practice. Additional studies of interest were identified by hand searches of bibliographies and cited reference tracking and consultation with clinical experts on the topic. The initial search was performed in October 2013 and the search was last updated on 2 June 2014.

Study Eligibility and Selection Criteria
Two authors (M.A.K. and A.S.L.) sequentially determined study eligibility. Studies were initially screened by the first author; decisions about study inclusion were made independently by both authors (M.A.K and A.S.L). Differences in opinion regarding study inclusion were resolved through consensus. Studies were included if they: (i) included human studies with participants 18 years of age or older; (ii) systematically evaluated predictors of fibrosis progression and/or clinical outcomes for patients with CHC; and (iii) used a longitudinal cohort study design. We focused on studies of untreated patients but also included studies with a mix of treated and untreated patients provided that <20% of the study population achieved SVR and results were stratified by treatment outcomes. For studies evaluating predictors of fibrosis progression, we selected studies only when paired biopsy was used to assess progression.

We excluded studies that enrolled (i) patients co-infected with hepatitis B (HBV) or human immunodeficiency virus (HIV); (ii) patients with additional causes of chronic liver disease; (iii) patients with prior liver transplantation and (iv) specific groups of patients (e.g. thalassaemia patients) only. These patient populations were excluded because they likely have different rates and risk factors for disease progression compared to the general population of patients with CHC. In addition, studies that evaluated HCC as the only outcome of interest were excluded as we were interested in broad clinical outcomes for patients with CHC, and predictors of HCC development alone may not be the same as predictors of disease progression in CHC in general. Lastly, studies that focused on predictors that are not readily available clinically (e.g. genetic or other serum markers for which commercial assays are not available, and experimental imaging techniques) were excluded given that they would not be relevant to current clinical practice.

Definition of Variables and Outcomes
Patients with CHC were defined as those with detectable HCV ribonucleic acid (RNA). We were interested in two outcomes: histological progression and clinical progression. The definition of histological progression was an increase of ≥1 METAVIR (range 0–4) or Ishak (range 0–6) fibrosis stage on follow-up liver biopsy. The definition of clinical progression encompassed the progression from compensated to decompensated cirrhosis, and liver-related or overall mortality. The definition of compensated cirrhosis was based on histology when available (Ishak fibrosis score ≥5 or METAVIR 4) or on the combined results of other noninvasive testing including laboratory tests and imaging. Decompensated cirrhosis was defined by the presence of any of the following: ascites, spontaneous bacterial peritonitis (SBP), variceal bleeding or hepatic encephalopathy (HE). The presence of HCC as defined by histology or American Association for Study of Liver Diseases radiological criteria was variably included as a clinical outcome.[10]

Data Abstraction and Validity Assessment

Data from eligible studies were abstracted by two authors (M.A.K. and S.Y.) using a standardised template adapted from the Cochrane Collaboration.[11] For all studies, we recorded: study design, sample size, patient population characteristics, duration of follow-up, predictor variables studied, outcomes measured, criteria used to define these outcomes and measures of association/predictiveness of risk for these outcomes. We accepted the outcome definitions as stated by each study without independently validating or reviewing their data. Study authors were directly contacted for additional, unpublished data.

Assessment of Risk of Bias and Study Quality
Two authors (M.A.K and S.Y.) independently assessed the risk of study bias and study quality. Since all the included studies were nonrandomised cohort studies, the Newcastle-Ottawa scale was used to judge study quality as recommended by the Cochrane Collaboration.[12] This scale uses a star system to assess the quality of a study based on three domains: selection of the study population, comparability of the study groups and method of outcomes assessment. For our review, given that no study had a comparison group, we excluded comparability components of the scale across all studies. Studies which received stars in every domain were assessed as being of high quality.

Data Synthesis and Analysis
Given the substantial variation in the design, methods and inclusion/exclusion criteria within our included studies, meta-analysis was not performed. Two authors (M.A.K. and S.Y.) qualitatively synthesised the results of the included studies, focusing on the risk factors evaluated and their independent predictiveness in terms of the outcomes measured and patient populations studied. Studies were categorised according to the outcome of interest: predictors of histological progression, predictors of clinical outcomes or studies investigating both clinical and histological outcomes. All authors had access to the study data and had reviewed and approved the final manuscript.

Studies Included in the Systematic Review
After removal of duplicate entries, 2257 unique articles were identified by our systematic literature search (Figure 1). On the basis of abstract review, 69 were selected for full-text review. Two study authors classified 29 articles as meeting the predefined criteria for analysis. In total, these 29 studies included 5817 unique patients from 20 separate patient cohorts. Sixteen of these studies investigated predictors of histological progression, eight studies evaluated predictors of clinical outcomes, and the remaining five studies investigated both histological and clinical outcomes.[13–41] Fourteen studies included treatment-naïve patients only, five included both treatment-naïve and treatment-experienced patients, eight included treatment-experienced patients only, and two studies did not describe the treatment status of the patients. We contacted four authors to obtain additional unpublished data.

Click on image to enlarge

Flow diagram of studies included in the systematic review. aMany studies met multiple exclusion criteria. Each study was coded under a single criterion only. bIncludes animal models, paediatric populations, patients who had previously undergone liver transplant, patients with chronic liver disease other than HCV monoinfection, evaluation of only specific subsets of populations with CHC. cIncludes studies that were descriptive papers only, studies that did not specifically evaluate for predictors of histological or clinical progression, and studies that evaluated predictors that are not readily clinically available. dIncludes studies that focused on risk factors for the development of HCC only, and studies where some patients achieved SVR and the results were not stratified based on response to treatment.

Characteristics of Studies on Histological Progression
A total of 21 studies evaluated predictors of histological progression. The studies included populations from Europe (n = 10), Asia (n = 2), and North (n = 8) and South America (n = 1). Only one study was prospective with the remaining 20 being retrospective analyses of previously collected data. The sample size for included studies varied (range 36–622 patients) with the majority having <200 patients (n = 14). A number of studies had overlapping cohorts. Four studies were derived from the Hepatitis C Anti-viral Long-term Treatment Against Cirrhosis (HALT-C) cohort, a US multi-centre randomised controlled trial to evaluate the safety and efficacy of low dose pegylated IFN in CHC patients with advanced fibrosis who failed to respond to prior IFN therapy. Four other pairs of studies drew from the same cohort of patients.[17,21,25,29,33,35,38,41] These studies were included in the review despite overlapping cohorts given differences in predictors examined, outcomes evaluated and criteria for selection of subsets of patients analysed within the overall larger cohort. The average duration of follow-up ranged from a median of 2.5–10 years.

The studies had varied inclusion and exclusion criteria as detailed in Table 1. Among the non-HALT-C studies, 11 studies had explicit requirements for baseline Ishak/METAVIR fibrosis stage. Five studies required minimal or no fibrosis at baseline and the remaining six studies required lack of cirrhosis on initial biopsy. Only 14 studies described criteria used to determine adequacy of biopsy specimens. The majority of the studies had a single pathologist blinded to clinical data score the biopsies while the HALT-C study had a panel of pathologists review the biopsies and consensus staging was recorded. Exclusionary alcohol intake was described in nine studies though the cut-off amounts and methods for ascertaining alcohol intake varied across the studies. The studies were predominately comprised of male patients in their late 30s to early 50s.

Characteristics of Studies of Clinical Outcomes
A total of 13 studies evaluated predictors of clinical outcomes. Six studies were conducted in the US (including 5 HALT-C studies), five in Europe and two in Asia. Only two studies were prospective with the remaining 11 being retrospective analyses. Sample size in each study varied from 52 to 1457 patients. Apart from the HALT-C studies, there was only one additional overlapping cohort.[36,37] The average duration of follow-up ranged from a median of 2.3 to a maximum of 14.4 years. Compared to studies on histological progression, the studies on clinical outcomes consisted of patients who were older, had more advanced fibrosis at baseline, and were more likely to be treatment experienced.

Incidence of Histological Progression
A summary of the specific outcomes evaluated and incidence of these outcomes in each study is displayed in Table 2, Table 3 and Table 4. For studies where the outcome was defined as ≥1 fibrosis stage increase on follow-up biopsy (n = 13), the incidence of that outcome ranged from 21–61% over a range of follow-up of 2.5–10 years.[14,16,18,21,25,28–33,35,41] Studies applying a stricter definition of fibrosis progression (≥2 stage increase on follow-up biopsy, n = 3) had less variability in range of incidence of outcome, reporting 22–34% over a range of follow-up of 3.5–5.8 years.[13,23,26] Studies with higher rates of fibrosis progression tended to have longer follow-up durations (>6 years), though there were several studies with follow-up of ≥6 years that had low rates of fibrosis progression. No identifiable differences in patient characteristics between studies with high vs. low incidence of fibrosis progression were noted.

Incidence of Clinical Progression
Studies assessing risk factors for clinical progression (n = 13) included several distinct outcomes. Four studies evaluating progression from compensated to decompensated cirrhosis reported an incidence between 13% and 40% over a range of follow-up of 2.3–14.4 years.[15,24,31,34] No clear pattern was identified between length of follow-up or patient characteristics and rate of outcomes. Notably, the definition of decompensation varied across studies. Four studies evaluating the incidence of overall mortality reported incidences between 8% and 47%. The range of follow-up for these studies was 3.9–14.4 years, with a higher rate of outcomes reported in studies with longer duration of follow-up.[15,27,39,40] The remaining studies used an aggregate outcome encompassing a broad range of clinical end points including decompensation, increase in Child–Turcotte–Pugh score, development of HCC, liver transplant and liver related as well as overall mortality. The reported incidence of this aggregate outcome was 13–31% over a range of follow-up of 3.5–6.3 years.[19,20,23,26,36,37]

Predictors of Histological Progression
A detailed list of the predictors evaluated and the results of univariate analysis is provided in Tables S3–S5 For each study, the predictor variables were categorised as follows: (i) baseline clinical characteristics including demographics and relevant co-morbidities; (ii) baseline laboratory results; (iii) baseline histological features or (iv) longitudinal laboratory and histology results.
All studies investigating predictors of histological progression evaluated baseline clinical characteristics, baseline laboratory results and baseline histology results except for Tamaki et al. who did not evaluate baseline histological features.[38] Only half of the studies evaluated longitudinal variables which were predominantly serial aminotransferase levels. Longitudinal biopsy results such as changes in steatosis score or histological activity index (HAI) were assessed in only five studies.[16,22,28–30] The predictors that were most consistently evaluated are listed in Figure 2a. The most common clinical characteristics assessed were age, gender, HCV genotype, alcohol intake, body mass index (BMI) and biopsy interval, and the most common laboratory values evaluated were platelet count and ALT levels. Baseline histological features were also frequently investigated predictors and were included in >70% of studies.

Click on image to enlarge

Figure 2.
List of variables identified to have significant predictive value for (a) histological and (b) clinical progression.

Multivariable analysis was performed in all but two studies.[19,31] Variables found to be independently predictive of histological progression are listed in Table 2 and Table 4. Among all the variables assessed, baseline steatosis was most consistently reported as independently predictive of subsequent fibrosis progression (significant on multivariate analysis in 6 of 21 studies) with an odds ratio (OR) [(95% confidence interval (CI)] of 4.8 (1.3–18.3) to 14.3 (2.1–111.1).[12,16,18,20,24,27] Notably, one study found that effect of baseline steatosis on fibrosis progression was dependent on baseline fibrosis stage.[20] Baseline Ishak/METAVIR fibrosis stage was the next most consistently identified independent predictor of histological progression (significant on multivariable analyses in five of 21 studies).[20,25,30,33,35] Only one of these studies reported the effect size, with adjusted relative risk of 1.93 (95% CI 1.3–9.0).[35] Figure 2a depicts the number of studies in which individual variables were significantly or not significantly predictive of histological progression on multivariate analyses.

Predictors of Clinical Outcomes
All 13 studies examining predictors of clinical outcomes included baseline clinical characteristics and laboratory results (Tables S4 and S5 Baseline histology was assessed in only eight studies though biopsies were performed in every study. Only three studies incorporated longitudinal data which consisted of serial laboratory values only.[23,24,36] The predictors that were most consistently evaluated are listed in Figure 2B. The most common clinical characteristics assessed were age, gender and BMI; the most common laboratory values evaluated were platelet count and ALT level.

Multivariable analysis was performed in all but two studies.[19,31] The variables found to be independently predictive of clinical progression are listed in Table 3 and Table 4. Among the variables assessed, baseline platelet count was the most consistent independent predictor of clinical outcomes (significant on multivariate analysis in six of 13 studies) followed by age, baseline AST/ALT ratio, albumin and bilirubin (each significant in four studies).[15,24,26,36,37,39] Figure 2B depicts the number of studies in which individual variables were significantly or not significantly predictive of clinical outcomes in multivariate analyses.

Mathematical Prediction Models

Five studies provided prediction models, three for fibrosis progression and four for clinical outcomes (Table S6[23,26,32,39,40] Four of the models were derived from the HALT-C study. All the prediction models are primarily comprised of baseline laboratory results. Only one of the models incorporated longitudinal data. None of the models had been validated in external CHC cohorts and only two models reported the associated area under the receiver operating characteristic curve.[23,40]

Quality Assessment and Risk of Bias
Studies evaluating predictors of histological progression were of varying quality, whereas studies investigating predictors of clinical outcomes or studies investigating combined outcomes were all of high quality except for one study.[31] Six studies on histological progression included a small number of patients with advanced fibrosis or cirrhosis on initial biopsy who were not able to progress according to the author's definition.[17][18, 25, 28, 33, 38] Two studies evaluated select cohorts (Levine et al. evaluated untreated Irish women who acquired HCV infection during pregnancy only, and Livingston et al. evaluated only treatment naïve Alaska Native and American Indian persons) and were scored as having limited representativeness.[30,31] The remaining studies were scored as being at least somewhat representative of the average patient with CHC in the community (Table S2

Although there is abundant literature on the topic of predictors of histological and clinical outcomes for patients with CHC, only 29 studies met our inclusion criteria which captured studies with a longitudinal study design in broad patient populations. Within the 29 studies included, the incidence of outcomes varied widely: 16–61% during a median follow-up of 2.5–10 years for fibrosis progression; 13–40% over 2.3–14.4 years for hepatic decompensation; and 8–47% over 3.9–14.4 years follow-up for overall mortality. The wide range in incidence of outcomes highlights the heterogeneity in patient population evaluated, stage of liver disease at enrollment, duration of follow-up, and definition of outcomes. Interestingly, higher rates of outcomes did not clearly correlate with longer durations of follow-up or more advanced disease at baseline across studies, pointing to more complex underlying interactions driving outcomes. Although the incidence data were not conducive to providing consensus outcome rates, we were able to identify risk factors that have most consistently been associated with outcomes of interest. Baseline steatosis and fibrosis score were the most consistent predictors of fibrosis progression and baseline platelet count, AST/ALT ratio, albumin, bilirubin and patient age were the most consistent predictors of clinical outcomes.
The variables identified as being most predictive of outcomes were not unexpectedly markers of more advanced liver disease. Though the overall finding that patients with more advanced disease are at higher risk for adverse outcomes is not novel, our study is the first to systematically identify the specific risk factors from among the many markers of advanced liver disease that portends worse prognosis. For example, among the laboratory markers of more advanced liver disease, platelet count, bilirubin, albumin and AST/ALT ratio conveyed meaningful risk information whereas INR, AST, ALT and MELD score did not. Differences in study design made it difficult to identify clear cut-off values for each predictor apart from platelet count with values ≤150 000/uL consistently associated with worse prognosis. Furthermore, individual laboratory markers may be less reliable in predicting outcomes than panels of markers such as aspartate aminotransferase to platelet ratio index (APRI), FIB-4, Fibrotest and/or measurements of liver stiffness. The finding that patients with more advanced disease have greater risk of disease progression suggests there may be subsets of patients who are rapid progressors. Understanding whether some patients are destined to be rapid progressors and being able to identify these patients at an early stage will help target limited resources to treat those patients who will derive the most benefit. Though none of the existing predictive models have been externally validated, the model developed by Ghany and colleagues is most readily applicable in clinical practice as it is based on routinely available data and evaluates important liver-related clinical outcomes.[26]

Examining the results in more detail yielded several useful insights. First, the finding of steatosis as a predictor of outcomes highlights a potential modifiable risk factor associated with disease progression. This is particularly relevant given the evolving obesity epidemic. Our data suggest that patients may benefit from aggressive lifestyle interventions in addition to other standard of care treatment for patients with CHC. The prognostic information gained from baseline liver biopsy results suggests that liver biopsies not only provide information regarding current staging of liver disease but also useful prognostic information. As performance of liver biopsies continue to decline, evaluating whether noninvasive assessment of fibrosis and steatosis will provide the same prognostic information would be important. Though only one study included in our review used an additional modality to assess liver fibrosis in conjunction with biopsy, this study showed that liver stiffness measurements were associated with overall mortality.[40]

Our review also highlights several areas for improvement for future studies on predictors of disease progression in CHC. Analysis of the individual predictive value of each risk factor found that there was a notable lack of incorporation of longitudinal variables. In the few studies that did assess longitudinal data, these variables were usually restricted to laboratory values, predominantly AST and ALT levels. These models do not mirror clinical practice where assessments of risk of disease progression are based on the pattern of a patient's test results over time. Models restricted to only baseline data also cannot distinguish between patients with similar initial data but who go on to have distinct disease courses and outcomes. Future studies can also benefit from implementing standardised definitions and criteria for outcomes and employing a panel of investigators to adjudicate outcomes as the variability in definition of predictor and outcome variables was one of the biggest challenges.

There are other limitations to our review such as sample selection bias, sampling error and misclassification bias in studies requiring paired biopsies. In the majority of studies, biopsies were assessed by a single pathologist and criteria for adequacy of biopsies was described in only 14 of 21 studies. Finally, the variability in duration of follow-up impacts not only incidence rates of outcomes but also predictiveness of variables examined.

In summary, this systematic review demonstrated that while there is an abundance of literature on factors associated with histological and/or clinical progression in CHC, there is a lack of longitudinal studies of representative, untreated, well characterised patients followed for a sufficiently long duration to allow the development of simple prediction models. Despite the limitations inherent to the existing literature, we were able to identify specific risk factors that have been consistently identified as being independently predictive of disease progression. By selecting studies consisting of broad patient populations and those that evaluated routinely obtained clinical data, our findings can be generalised to and applied in many clinical settings. From a policy standpoint, we have highlighted that it is possible to identify patients at higher risk for adverse outcomes. Policies that target costly new HCV therapies to these patients who would derive the most benefit will maximise their cost effectiveness. The availability of risk prediction tools that can be applied in the clinic will help both physicians and patients decide whether to embark on HCV treatment now or to wait for more affordable treatment. These types of tools will be particularly important in resource-limited countries and must therefore be validated in broad patient populations.


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Thursday, October 16, 2014

Watchful Waiting: Role of Disease Progression on Uncertainty and Depressive Symptoms in Patients With Chronic Hepatitis C

Journal of Viral Hepatitis
Watchful Waiting: Role of Disease Progression on Uncertainty and Depressive Symptoms in Patients With Chronic Hepatitis C

J. P. Colagreco, D. E. Bailey, J. J. Fitzpatrick, C. M. Musil, N. H. Afdhal, M. Lai

J Viral Hepat. 2014;21:727-733.

Watchful Waiting in Chronic Hepatitis C

Discussion Only
View Abstract, IntroductionMaterials and MethodsSubjects, and Results @ Medscape

We found a substantial rate of illness uncertainty (54%) and depressive symptoms (40%) in our cohort of patients with CHC on watchful waiting, consistent with the prior studies.[15,16] Surprisingly, the histological data did not correlate with overall illness uncertainty and depressive symptoms. The stage of fibrosis was significantly related to the Complexity subscale of illness uncertainty, but not to the overall illness uncertainty score or other illness uncertainty subscales. Clinicians often make recommendations for the patient to defer treatment and offer reassurances about their minimal and/or stable disease based on liver biopsy. However, reassuring histological data do not seem to lower the patients' feelings of illness uncertainty or depressive symptoms. Recognizing this paradox is important for clinicians and points to the need for additional research about how patients process relevant medical information.

We confirmed the previous finding of the association between overall illness uncertainty and depressive symptoms in patients with CHC following watchful waiting with a similar mean uncertainty score (86.5 vs 87.1).[17] Bailey et al.[17] found that patients with CHC following watchful waiting experience depressive symptoms associated with illness uncertainty. In his study on uncertainty, symptoms, and quality of life in patients with CHC, three constructs of illness uncertainty, Ambiguity, Inconsistency and Complexity, were significantly related to depressive symptoms. Unpredictability, another construct of illness uncertainty, was not significantly related to depressive symptoms.[17] In our study, we also found the Ambiguity and Inconsistency subscale scores to be positively significantly correlated with the CES-D scores, indicating a strong positive relationship between inconsistency and ambiguity in illness and depressive symptoms (See Table 3). The high rates of depressive symptoms and the correlation of the depressive symptoms to illness uncertainty point to the importance of illness uncertainty (especially the Ambiguity and Inconsistency components) as a possible target for intervention.

This correlational study was not designed to show clear cause and effect. While illness uncertainty is correlated with depressive symptoms, it is unclear whether illness uncertainty contributes directly to depressive symptoms or whether those who have depressive symptoms have higher levels of illness uncertainty because of their depressed disposition. It may be the case that those patients with depressive symptoms have higher levels of illness uncertainty and that the correlations are related to personality traits or neuropsychiatric attributes than knowledge of the disease or the extent of disease present. An intervention study to reduce illness uncertainty might help elucidate the causal relationship between illness uncertainty and depressive symptoms if the reduction of illness uncertainty resulted in decreased depressive symptoms. Measuring illness uncertainty before and after liver biopsy, and after treatment might also provide insight into the causal relationship of the two variables.

There is also data showing that patients with CHC experience cognitive impairment (in the areas of concentration, working memory, sustained attention and processing speed) and have cerebral metabolite abnormalities suggestive of frontal–subcortical dysfunction.[22–24] Patients with CHC were found to be impaired on more cognitive tasks than those who cleared hepatitis C, suggesting a direct viral effect. While these studies looked at cognitive function rather than depressive symptoms and illness uncertainty, they raise the questions of whether the depressive symptoms and illness uncertainty seen in patients with CHC might be from a direct viral effect and whether clearance of hepatitis C leads to decreased depressive symptoms and illness uncertainty because of its direct affect on the brain. Answering these questions would require brain imaging to be part of future studies.

Recent new information regarding medication advancements in hepatitis C treatment likely contributed to higher scores on the Inconsistency subscale of the MUIS-A for this population as new therapies were emerging at the time data were collected for this study. Advancement in treatment for HCV-infected patients probably raised concerns about the possible success or failure of viral eradication for this cohort, questions about the possibility of additional treatment advances, and concerns in general regarding the timing of treatment, the possibility of side effects of treatment and the duration of treatment. Some patients may have experienced more uncertainty, while others may have experienced less because hope for cure might have influenced uncertainty levels in both directions.

While the study was not powered to detect statistically significant differences in the scores between the different subgroups (reasons for deferral), the treatment naïve patients had lower mean scores on both the illness uncertainty and depressive symptoms scales. Additional studies with larger samples are required to explore the influence of the reasons for deferral on illness uncertainty and depressive symptoms.

There are no other studies available to provide insight into why the factors other than illness uncertainty might not have been significant in this population. More work is needed to determine the factors that cause and ameliorate patients' feelings of illness uncertainty and depressive symptoms while in watchful waiting. Qualitative studies designed to understand illness uncertainty in patients with hepatitis C on watchful waiting could provide insight into the illness experience of patients in this population. This insight can, in turn, help researchers design intervention studies using the Theory of Uncertainty in Illness, as has been carried out in populations who have other diseases.[25–29] We also hope to reassess illness uncertainty and depressive symptoms in this cohort of patients on follow-up after they have been treated to determine whether those who are cured have a decrease in their illness uncertainty and depressive symptoms.

With more efficacious and tolerable therapies on the horizon, many patients are advised to defer treatment. Given this population's high risk for illness uncertainty and depressive symptoms, part of the informed deferral process should be assessment for illness uncertainty and depressive symptoms.

In conclusion, we found that reassuring histological data were not correlated with less depressive symptoms and illness uncertainty in patients with CHC on watchful waiting. Clinicians who advise patients to defer treatment should be aware of the possibility of the symptoms and address them.

Tuesday, May 20, 2014

Risk factors for liver-related mortality in chronic hepatitis C patients: A deceased case-living control study

World J Gastroenterol. May 14, 2014; 20(18): 5519–5526.
Published online May 14, 2014. doi:  10.3748/wjg.v20.i18.5519
PMCID: PMC4017067

Risk factors for liver-related mortality in chronic hepatitis C patients: A deceased case-living control study

To investigate the risk factors for liver-related mortality in chronic hepatitis C (CHC) patients

All deceased CHC inpatient data were collected from the Beijing 302 Hospital clinical database, which includes more than 8250 CHC inpatients during the period from 2002 to 2012. The controls were matched to cases by age (± 2 years), sex and date of hospital admission (within the same year). Potential risk factors were included for the evaluation, and odds ratios (OR) and 95%CI were estimated using univariate (unadjusted) and multivariate (adjusted OR, AOR) conditional logistic regression. All statistical tests were two-sided. P values < 0.05 were considered statistically significant.

Based on examinations of 144 CHC-related deceased cases and 576 controls, we found that antiviral therapy with interferon-α was associated with a 47% decrease in the risk of hepatic mortality (AOR = 0.53, 95%CI: 0.28-0.99, P = 0.048). Additionally, the initial diagnostic stage of the disease (AOR = 2.89, 95%CI: 1.83-4.56 and P < 0.001 for liver cirrhosis/AOR = 8.82, 95%CI: 3.99-19.53 and P < 0.001 for HCC compared with CHC), diabetes (AOR = 2.35, 95%CI: 1.40-3.95, P = 0.001), hypertension (AOR = 1.76, 95%CI: 1.09-2.82, P = 0.020), alcohol consumption (AOR = 1.73, 95%CI: 1.03-2.81, P = 0.037) and HBsAg positivity (AOR = 22.28, 95%CI: 5.58-89.07, P < 0.001) were associated with a significant increase in the risk of liver-related mortality in CHC patients.

This study indicates that interferon-α treatment, the stage at the initial diagnosis of the disease and comorbidities are all independent risk factors for liver-related mortality in CHC patients. 

Core tip: Many previous studies have suggested that several complex factors have an important impact on hepatitis C virus-related mortality. However, the evaluation of such factors using a deceased case-living control study with a large number of patients has not been reported. The aim of the present study was to investigate the risk factors for liver-related mortality in chronic hepatitis C (CHC) patients using a deceased case-living control study design. This study indicates that interferon-α plus ribavirin treatment, the stage at the initial diagnosis and comorbidities are all independent risk factors for liver-related mortality in CHC patients. 

Discussion Only
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In this case-control based study, the use of interferon and ribavirin for at least 12 wk was associated with a 47% decrease in liver-related mortality among CHC patients. We also found that there was a significant trend toward an increasing liver-related mortality in patients with HBsAg positivity, diabetes, hypertension, alcohol consumption and initial diagnosis at an advanced stage after controlling for potential confounders.

Chronic HCV infected cases are associated with higher mortality rates compared to non-infected individuals[23-26], which suggests that those with chronic HCV infection are at a higher risk of death and should be closely monitored. Previous studies have suggested that gender and age may influence the prognosis of CHC[3,15,27,28]; thus, the controls in the present study were matched by chronic HCV infection, gender, age and date of hospital admission to control for confounders. These variables were excluded from the statistic models. Patients with an early diagnosis of chronic HCV infection may have a better outcome, and a previous study showed that CHC-related cirrhosis increased the rate of mortality nearly four-fold compared to CHC patients without cirrhosis[15]. In our study, this rate was 2.89, while patients with HCC had a liver-related mortality 8.82 times higher than CHC patients after adjusting for confounders.

Chronic HCV infection does not have a significant impact on all-cause mortality in the first decade of infection[29]; however, liver disease progression is accelerated in the presence of cofactors such as HBV infection[2]. HBsAg positivity for longer than 6 mo is the most important indicator of chronic HBV infection, and anti-HBc positivity indicates past exposure to HBV. Previous studies have suggested that anti-HBc is not related to the prognosis of HCV infection[20,21]. In the present study, HBsAg and anti-HBc were associated with an increased rate of mortality in an unadjusted univariate analysis model; however, after adjusting for the confounders, only HBsAg remained an independent risk factor for CHC mortality. Additionally, chronic alcohol consumption in the presence of obesity and viral hepatitis could damage the liver[30]. Several studies have indicated that obesity and alcohol synergistically increase the risk of HCC and death[7,31-33]. In addition, smoking is always considered a risk factor for disease progression and poor prognosis[8,34,35], although controversial results have been reported[22]. In the present study, we found that alcohol consumption is associated with an increased risk of mortality in both univariate and multivariate analyses. In contrast, smoking was not related to mortality in either analysis. This result indicates that abstinence from habitual alcohol drinking is more directly beneficial for liver-related outcomes. Two studies have shown that diabetes was relevant to the mortality of CHC patients[6,36], and this relationship was confirmed in the present study. Furthermore, there are no data, to our knowledge, concerning the association between hypertension and the risk of HCV-related death. We found that hypertension is an independent risk factor for the increase of liver-related CHC mortality.

Antiviral therapy with interferon-α and ribavirin has been the standard of care for CHC, and among those who achieve sustained virologic response, 99% permanently remain HCV RNA-negative[37]. Many studies have suggested that interferon therapy is associated with decreased mortality, even in patients with cirrhosis[11,12,14,18,19]. There have also been reports demonstrating that the rate of progression to HCC was lowered two-fold following treatment with at least 3 × 106 IU interferon three times a week for 3 mo, regardless of the biological and virologic responses[38]. In contrast, a different study indicated that interferon-α did not affect the survival of patients with CHC[13]. However, most of these studies included very few deceased patients. In the present study, we included 144 deceased CHC inpatients for evaluation and found that patients treated with combination therapy had increased survival. To our knowledge, using this case-control study method, these are the first data showing that patients treated with interferon for at least 12 wk have reduced mortality.

The relative influence of routes of infection on the prognosis of liver disease remains controversial[22,39-42]. Additionally, whether transfusion-associated HCV and a family history of viral hepatitis are associated with a higher risk of mortality than other routes is largely unknown. The results of the present study indicate that neither the blood transfusion history nor a family history of viral hepatitis are associated with an increased risk of mortality, as indicated by both univariate and multivariate analyses.

Several limitations of the present study should be noted. First, we did not have access to information on the socioeconomic status of the subjects. It is difficult to investigate the real economic status in many patients, although a previous study showed that it impacts the prognosis of CHC patients[43]. Second, although we involved many potential factors in the statistical analysis, a number of other possible confounding variables, such as body mass index, were not included in our model because of the potential interaction with alcohol. Third, not all direct causes of death of the deceased patients were obtained from postmortem examinations due to a lack of family permission. Fourth, anti-HIV antibody status was initially included in this study; however, all cases and controls were negative for anti-HIV antibodies, and evaluating this factor was thus not possible. Fifth, HCV RNA was not determined in 16.67% (24) of cases and 1.91% (11) of controls at their last index date because HCV RNA in the case group was collected from the last admission of cases, which included some cases with bleeding varices and hepatic encephalopathy, and nearly all of the patients died shortly after this time point. At this urgent point, HCV RNA is unable to guide the treatment options; thus, HCV RNA was not determined in these 24 cases. Sixth, accurately measuring the cumulative intake of tobacco smoke and alcohol was not possible, which makes further stratification and analysis difficult. Seventh, because the initial diagnostic stage is a potential risk factors involved in assessment, it is improper to consider this a matched factor, which results in disproportionate stages between the two groups. Finally, as with any observational study, residual confounding by unmeasured factors that are different between cases and controls is possible. However, the confounding effect of medical attention could be corrected for by hospitalization, and all of the subjects in this study were inpatients.

In summary, our study demonstrates that the initial diagnostic stage of disease and comorbidities, including HBsAg seropositive status, alcohol consumption, diabetes and hypertension, are independent risk factors for liver-related mortality, whereas antiviral therapy decreases the risk of liver-related mortality in CHC patients. To our knowledge, this study is the first to investigate the risk of CHC mortality using a deceased case-living control study design and the first to indicate that hypertension may be a risk and antiviral therapy for a period of at least 12 wk may be beneficial for liver-related CHC mortality. We suggest that physicians should consider the above-mentioned conditions during disease evaluation.

PMID:24833882 [PubMed - in process]
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