Tahany Awad

Peginterferon alpha‐2a is associated with higher sustained virological response than peginterferon alfa‐2b in chronic hepatitis C: Systematic review of randomized trials

A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha‐2a or peginterferon alfa‐2b) is most effective. We performed a systematic review of head‐to‐head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently extracted data from each eligible trial report. We statistically combined data using a random effects meta‐analysis according to the intention‐to‐treat principle. We identified 12 randomized clinical trials, including 5,008 patients, that compared peginterferon alpha‐2a plus ribavirin versus peginterferon alfa‐2b plus ribavirin. Overall, peginterferon alpha‐2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa‐2b (47% versus 41%; risk ratio 1.11, 95% confidence interval 1.04–1.19; P = 0.004 [eight trials]). Subgroup analyses of risk of bias, viral genotype, and treatment history yielded similar results. The meta‐analysis of adverse events leading to treatment discontinuation included 11 trials and revealed no significant differences between the two peginterferons. Conclusion: Current evidence suggests that peginterferon alpha‐2a is associated with higher SVR than peginterferon alfa‐2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm. (HEPATOLOGY 2010.)

Evolution of Heterogeneity (I2) Estimates and Their 95% Confidence Intervals in Large Meta-Analyses

Background Assessment of heterogeneity is essential in systematic reviews and meta-analyses of clinical trials. The most commonly used heterogeneity measure, I2, provides an estimate of the proportion of variability in a meta-analysis that is explained by differences between the included trials rather than by sampling error. Recent studies have raised concerns about the reliability of I2 estimates, due to their dependence on the precision of included trials and time-dependent biases. Authors have also advocated use of 95% confidence intervals (CIs) to express the uncertainty associated with I2 estimates. However, no previous studies have explored how many trials and events are required to ensure stable and reliable I2 estimates, or how 95% CIs perform as evidence accumulates. Methodology/Principal Findings To assess the stability and reliability of I2 estimates and their 95% CIs, in relation to the cumulative number of trials and events in meta-analysis, we looked at 16 large Cochrane meta-analyses - each including a sufficient number of trials and events to reliably estimate I2 - and monitored the I2 estimates and their 95% CIs for each year of publication. In 10 of the 16 meta-analyses, the I2 estimates fluctuated more than 40% over time. The median number of events and trials required before the cumulative I2 estimates stayed within +/−20% of the final I2 estimate was 467 and 11. No major fluctuations were observed after 500 events and 14 trials. The 95% confidence intervals provided good coverage over time. Conclusions/Significance I2 estimates need to be interpreted with caution when the meta-analysis only includes a limited number of events or trials. Confidence intervals for I2 estimates provide good coverage as evidence accumulates, and are thus valuable for reflecting the uncertainty associated with estimating I2.

Comparison of statistical inferences from the DerSimonian-Laird and alternative random-effects model meta-analyses - an empirical assessment of 920 Cochrane primary outcome meta-analyses.

In random-effects model meta-analysis, the conventional DerSimonian-Laird (DL) estimator typically underestimates the between-trial variance. Alternative variance estimators have been proposed to address this bias. This study aims to empirically compare statistical inferences from random-effects model meta-analyses on the basis of the DL estimator and four alternative estimators, as well as distributional assumptions (normal distribution and t-distribution) about the pooled intervention effect. We evaluated the discrepancies of p-values, 95% confidence intervals (CIs) in statistically significant meta-analyses, and the degree (percentage) of statistical heterogeneity (e.g. I(2)) across 920 Cochrane primary outcome meta-analyses. In total, 414 of the 920 meta-analyses were statistically significant with the DL meta-analysis, and 506 were not. Compared with the DL estimator, the four alternative estimators yielded p-values and CIs that could be interpreted as discordant in up to 11.6% or 6% of the included meta-analyses pending whether a normal distribution or a t-distribution of the intervention effect estimates were assumed. Large discrepancies were observed for the measures of degree of heterogeneity when comparing DL with each of the four alternative estimators. Estimating the degree (percentage) of heterogeneity on the basis of less biased between-trial variance estimators seems preferable to current practice. Disclosing inferential sensitivity of p-values and CIs may also be necessary when borderline significant results have substantial impact on the conclusion. Copyright

Data mining of routine laboratory tests can predict liver disease progression in Egyptian diabetic patients with hepatitis C virus (g4) infection: a cohort study of 71 806 patients

Objectives Hepatitis C virus (HCV) and diabetes mellitus (DM) are prevalent diseases worldwide, associated with significant morbidity, mortality, and mutual association. The aims of this study were as follows: (i) find the prevalence of DM among 71 806 Egyptian patients with chronic HCV infection and its effect on liver disease progression and (ii) using data mining of routine tests to predict hepatic fibrosis in diabetic patients with HCV infection. Patients and methods A retrospective multicentered study included laboratory and histopathological data of 71 806 patients with HCV infection collected by Egyptian National Committee for control of viral hepatitis. Using data mining analysis, we constructed decision tree algorithm to assess predictors of fibrosis progression in diabetic patients with HCV. Results Overall, 12 018 (16.8%) patients were diagnosed as having diabetes [6428: fasting blood glucose ≥126 mg/dl (9%) and 5590: fasting blood glucose ≥110–126 mg/dl (7.8%)]. DM was significantly associated with advanced age, high BMI and &agr;-fetoprotein (AFP), and low platelets and serum albumin (P⩽0.001). Advanced liver fibrosis (F3–F4) was significantly correlated with DM (P⩽0.001) irrespective of age. Of 16 attributes, decision tree model for fibrosis showed AFP was most decisive with cutoff of 5.25 ng/ml as starting point of fibrosis. AFP level greater than cutoff in patients was the first important splitting attribute; age and platelet count were second important splitting attributes. Conclusion (i) Chronic HCV is significantly associated with DM (16.8%). (ii) Advanced age, high BMI and AFP, low platelets count and albumin show significant association with DM in HCV. (iii) AFP cutoff of 5.25 is a starting point of fibrosis development and integrated into mathematical model to predict development of liver fibrosis in diabetics with HCV (G4) infection.

Reply: Methodological issues in a meta‐analysis

We read with great interest the article by Azzalini et al., who demonstrated that cigarette smoking worsens the severity of nonalcoholic fatty liver disease (NAFLD) in obese Zucker rats. In a related letter, Xu and coworkers showed that cigarette smoking may act as a cofactor but not as an independent factor for NAFLD in humans. However, currently it is uncertain whether there is a significant association between smoking patterns and the severity of liver histology among patients with NAFLD. Clarification of this aspect may help to explain the underlying mechanisms and may be of clinical importance in planning preventive and therapeutic strategies. We have therefore assessed whether there is a significant association between liver histology and smoking patterns among patients with biopsy-proven NAFLD. A total of 90 consecutive outpatients with NAFLD (43 males and 47 females, mean age, 47 6 8 years) were recruited from our clinics. All patients had chronically elevated liver enzymes and hepatic steatosis detected by ultrasonography. The NAFLD diagnosis was based on liver biopsy and exclusion of other known etiologic factors of chronic liver disease (alcohol abuse or intake 20 g/day, viral hepatitis, autoimmune hepatitis, and use of hepatotoxic drugs). An experienced pathologist blinded to clinical data scored the liver biopsies according to the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network scoring system. Pack-years of smoking were calculated as the product of the duration of smoking (in years) and the average number of cigarettes smoked per day. The protocol was approved by the local ethics committee, and all participants gave written informed consent. In multivariable-adjusted linear logistic regression models, each histological feature of NAFLD (i.e., steatosis grade, necroinflammatory grade, or fibrosis stage analyzed separately) was considered as the dependent variable. Sex, age, body mass index, smoking, low-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance (HOMA-IR) score, and metabolic syndrome (considered as a single clinical entity) were included as covariates. A total of 30 patients had ever smoked, 26 were past smokers, whereas 34 were current smokers. The distribution of nonsmokers, past smokers, and current smokers was not different in NAFLD patients classified according to liver histopathology (steatosis alone, borderline steatohepatitis, definite steatohepatitis). Notably, pack-years of smoking were not associated with degree of hepatic steatosis (P 1⁄4 0.67), necroinflammation (P 1⁄4 0.34), and fibrosis among patients with NAFLD (P 1⁄4 0.41). These results suggest that the severity of liver histopathology among patients with NAFLD is not associated with smoking patterns, after allowance for classical risk factors, insulin resistance, and the presence of the metabolic syndrome. This study has shown for the first time that the histological severity of NAFLD is not independently predicted by smoking patterns after adjustment for a broad spectrum of potential confounders, including the metabolic syndrome, a condition that is strongly correlated with NAFLD. Cigarette smoking is one of the major environmental factors suggested to play a crucial role in the development of several diseases. Disorders such as atherosclerosis, lung cancer, or cardiovascular diseases are highly associated with tobacco consumption. However, cigarette smoking does not seem to influence the histological features or the severity of NAFLD in a dosedependent fashion. The biological mechanisms by which smoking could contribute to progressive NAFLD in humans are still poorly understood. Future follow-up studies are necessary to validate these findings and better estimate the risk of disease progression in relation to smoking among patients with biopsy-proven NAFLD. YUSUF YILMAZ, M.D. OYA YONAL, M.D. RAMAZAN KURT, M.D. EROL AVSAR, M.D. Department of Gastroenterology Marmara University School of Medicine Altunizade, Istanbul, Turkey

Real-Life Comparison of Pegylated-Interferon 2a Versus 2b Combination Therapy of Chronic Hepatitis C Virus Reply

A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha-2a or peginterferon alfa-2b) is most effective. We performed a systematic review of head-to-head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently extracted data from each eligible trial report. We statistically combined data using a random effects meta-analysis according to the intention-to-treat principle. We identified 12 randomized clinical trials, including 5, 008 patients, that compared peginterferon alpha-2a plus ribavirin versus peginterferon alfa-26 plus ribavirin. Overall, peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa-26 (47% versus 41% ; risk ratio 1.11, 95% confidence interval 1.04-1.19 ; P = 0.004 [eight trials]). Subgroup analyses of risk of bias, viral genotype, and treatment history yielded similar results. The meta-analysis of adverse events leading to treatment discontinuation included 11 trials and revealed no significant differences between the two peginterferons. Conclusion: Current evidence suggests that peginterferon alpha-2a is associated with higher SVR than peginterferon alfa-2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm. (HEPATOLOGY 2010 ; 51:1176-1184.)

Proceed with Caution Peginterferon Alpha-2a versus Peginterferon Alfa-2b in Chronic Hepatitis C. A Systematic Review of Randomized Trials Reply

We read with great interest the article by Cavazza et al., who demonstrated that an advanced histological stage was the only risk factor associated with the development of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) from two European centers. Similar results were described in a Japanese multicenter study by Shibuya et al. Although these studies suggest screening for HCC in patients with advanced-stage PBC, it is still uncertain whether there is a significantly increased risk of HCC development in patients with stage IV PBC cirrhosis versus patients with cirrhosis of other etiologies. We assessed in a single-center study the incidence of HCC in North American patients with stage IV PBC or autoimmune hepatitis (AIH) cirrhosis and compared it to the incidence of HCC in patients with hepatitis C virus (HCV) cirrhosis. Three hundred fifteen patients with HCV cirrhosis, 49 patients with AIH cirrhosis, and 52 patients with stage IV PBC were evaluated at the Cleveland Clinic between 2001 and 2007. Stage IV PBC cirrhosis was diagnosed when patients had positive serological and histological findings of cirrhosis or biochemical and radiological evidence of portal hypertension. Cirrhosis due to AIH was defined by positive serological and histological findings of cirrhosis or biochemical and radiological evidence of portal hypertension. HCC-free survival was analyzed from the moment of the diagnosis of cirrhosis in HCV, AIH, and PBC patients until death or transplantation. During a median follow-up of 3.6 years (with 25th and 75th percentiles of 1.8 and 6.3, respectively), 64 of 315 patients (20.3%) with HCV cirrhosis, 2 of 49 patients (4.1%) with AIH cirrhosis, and 4 of 52 patients (7.7%) with PBC cirrhosis developed HCC. The annual cumulative incidence of HCC was 1.1% in patients with AIH cirrhosis, 1.5% in patients with PBC cirrhosis, and 4.0% in patients with HCV cirrhosis (Fig. 1). This study has shown that although patients with stage IV PBC cirrhosis develop liver cancer, the risk is significantly lower in comparison with the risk for patients with HCV cirrhosis. The results of our study are discordant with a previously reported Spanish series in which the risks of HCC were similar in patients with late-stage PBC and in patients with HCV cirrhosis. We agree with Cavazza et al. that the low prevalence of PBC and the possible influence of geography on disease progression are confounding factors that may explain the divergent results in the literature. Future multicenter studies in North America with a longer follow-up period are necessary to validate these findings and better estimate the risk of HCC in PBC patients at an advanced histological stage.

Hepatitis C intervention research – Where are we now and where should we be heading?

In this paper we outline some of the major pending research questions that lie ahead in hepatitis C intervention research. We argue why these should be answered with randomised clinical trials and we stress how Egypt and other Arab countries can play an important role in this context. We delineate a number of design issues relevant to recent and future hepatitis C randomised clinical trials and provide insights on how and why randomised clinical trial designed in a pragmatic and evidence-based framework will efficiently answer pending research questions.