Validation of a machine learning approach using FIB-4 and APRI scores assessed by the metavir scoring system: A cohort study.

BACKGROUND AND STUDY AIM: The study aim was to improve and validate the accuracy of the fibrosis-4 (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI) scores for use in a potential machine-learning (ML) method that accurately predicts the extent of liver fibrosis. PATIENTS AND METHODS: This retrospective multicenter study included 69,106 patients with chronic hepatitis C planned for antiviral therapy from January 2010-December 2014 with liver biopsy results. FIB-4 and APRI scores were calculated and their performance for predicting significant liver fibrosis (F3-F4) assessed against the Metavir scoring system. ML was used for feature selection and reduction to identify the most relevant attributes (CfsSubseteval/best first) for prediction. RESULTS: In this study, 57,492 (83.2%) patients were F0-F2, and 11,615 (16.8%) patients were F3-F4. The revalidation of FIB-4 and APRI showed lower accuracy and higher disagreement with the biopsy results, with AUCs of 0.68 and 0.58, respectively. FIB-4 diagnosed fewer (14%) F3-F4 patients, and the high specificity and negative predictive values of FIB-4 and APRI reflected the low prevalence of F3-F4 in the study population. Out of 15 attributes, age (>35 years), AFP (>6.5 ng/ml), and platelet count (<150,000/mm3) were the most relevant risk attributes, and patients with one or more of these risk factors were likely to be F3-F4, with a classification accuracy of ≤ 92% and receiver operating characteristics area of 0.74. CONCLUSION: FIB-4 and APRI scores were not very accurate and missed diagnosing most of the F3-F4 patients. ML implementation improved medical decisions and minimized the required clinical data to three risk factors.

Incidence, prevalence and risk factors for hepatitis C in Danish prisons.

Hepatitis C virus (HCV) infection is prevalent among people in prison and prisons could therefore represent a unique opportunity to test risk groups for HCV. The aim of this sero-epidemiological study was to determine the incidence and prevalence of HCV infection and the corresponding risk factors in Danish prisons. Participants, recruited from eight Danish prisons, were tested for HCV using dried blood spots and filled out a questionaire with demographic data and risk factors for HCV infection. In total, 76.9% (801/1041) of all eligible prisoners consented to participate. The prevalence of HCV RNA positive prisoners was 4.2% (34/801) and the in-prison incidence rate was 0.7-1.0 per 100PY overall and 18-24/100PY among PWIDs. Infected prisoners were older than the overall population with a mean age of 42 years and only 17.6% (6/34) were younger than 35 years. The prevalence of PWID was 8.5% (68/801) and only 3% (2/68) of PWID were younger than 25 years. Among the PWID, 85.3% (58/68) had ever received opioid substitution therapy (OST) and 47.1% (32/68) were currently receiving OST. Risk factors associated with HCV infection were intravenous drug use, age ≥ 40 years, and being incarcerated ≥ 10 years. In conclusion, the prevalence of PWID in Danish prisons is low, possibly reflecting a decrease in injecting among the younger generation. This together with OST coverage could explain the low prevalence of HCV infection. However among PWIDs in prison the incidence remains high, suggesting a need for improved HCV prevention in prison.

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 α-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.

Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C.

BACKGROUND: A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin still represents standard treatment of chronic hepatitis C infection in the majority of patients. However, it is not established which of the two licensed peginterferon products, peginterferon alpha-2a or peginterferon alpha-2b, is the most effective and has a better safety profile. OBJECTIVES: To systematically evaluate the benefits and harms of peginterferon alpha-2a versus peginterferon alpha-2b in head-to-head randomised clinical trials in patients with chronic hepatitis C. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until October 2013. We also searched conference abstracts, journals, and grey literature. SELECTION CRITERIA: We included randomised clinical trials comparing peginterferon alpha-2a versus peginterferon alpha-2b given with or without co-intervention(s) (for example, ribavirin) for chronic hepatitis C. Quasi-randomised studies and observational studies as identified by the searches were also considered for assessment of harms. Our primary outcomes were all-cause mortality, liver-related morbidity, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. The secondary outcome was sustained virological response in the blood serum. DATA COLLECTION AND ANALYSIS: Two authors independently used a standardised data collection form. We meta-analysed data with both the fixed-effect and the random-effects models. For each outcome we calculated the relative risk (RR) with 95% confidence interval (CI) based on intention-to-treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risks of random errors (play of chance). Intervention effects on the outcomes were assessed according to GRADE. MAIN RESULTS: We included 17 randomised clinical trials which compared peginterferon alpha-2a plus ribavirin versus peginterferon alpha-2b plus ribavirin in 5847 patients. All trials had a high risk of bias. Very few trials reported data on very few patients for the patient-relevant outcomes all-cause mortality, liver-related morbidity, serious adverse events, and quality of life. Accordingly, we were unable to conduct meta-analyses on all-cause mortality, liver-related morbidity, and quality of life. Twelve trials reported on adverse events leading to discontinuation of treatment without clear evidence of a difference between the two peginterferons (197/2171 (9.1%) versus 311/3169 (9.9%); RR 0.84, 95% CI 0.57 to 1.22; I2 = 44%; low quality evidence). A trial sequential analysis showed that we could exclude a relative risk reduction of 20% or more on this outcome. Peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response in the blood serum compared with peginterferon alpha-2b (1069/2099 (51%) versus 1327/3075 (43%); RR 1.12, 95% CI 1.06 to 1.18; I2= 0%, 12 trials; moderate quality evidence). Trial sequential analyses supported this result. Subgroup analyses based on risk of bias, viral genotype, and treatment history yielded similar results. Trial sequential analyses supported the results in patients with genotypes 1 and 4, but not in patients with genotypes 2 and 3. AUTHORS' CONCLUSIONS: There is lack of evidence on patient-important outcomes and paucity of evidence on adverse events. Moderate quality evidence suggests that peginterferon alpha-2a is associated with a higher sustained virological response in serum than with peginterferon alpha-2b. This finding may be affected by the high risk of bias of the included studies . The clinical consequences of peginterferon alpha-2a versus peginterferon alpha-2b are unknown, and we cannot translate an effect on sustained virological response into comparable clinical effects because sustained virological response is still an unvalidated surrogate outcome for patient-important outcomes. The lack of evidence on patient-important outcomes and the paucity of evidence on adverse events means that we are unable to draw any conclusions about the effects of one peginterferon over the other.

Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C.

BACKGROUND: Pegylated interferon (peginterferon) plus ribavirin is the recommended treatment for patients with chronic hepatitis C, but systematic assessment of the effect of this treatment compared with interferon plus ribavirin is needed. OBJECTIVES: To systematically evaluate the benefits and harms of peginterferon plus ribavirin versus interferon plus ribavirin for patients with chronic hepatitis C. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index-Expanded, and LILACS. We also searched conference abstracts, journals, and grey literature. The last searches were conducted in September 2013. SELECTION CRITERIA: We included randomised clinical trials comparing peginterferon plus ribavirin versus interferon plus ribavirin with or without co-intervention(s) (e.g., other antiviral drugs) for chronic hepatitis C. Quasi-randomised and observational studies retrieved through the searches for randomised clinical trials were also considered for reports of harms. Our primary outcomes were liver-related morbidity, all-cause mortality, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. Our secondary outcome was sustained virological response in serum, that is, undetectable hepatitis C virus RNA in serum by sensitive tests six months after the end of treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently used a standardised data collection form. We meta-analysed data with both fixed-effect and random-effects models. For each outcome, we calculated the odds ratio (OR) (for liver-related morbidity or all-cause mortality) or the risk ratio (RR) along with 95% confidence interval (CI) based on intention-to-treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risk of random errors (play of chance).For each outcome, we calculated the RR with 95% CI based on intention-to-treat analysis. Effects of interventions on outcomes were assessed according to GRADE. MAIN RESULTS: We included 27 randomised trials with 5938 participants. All trials had high risk of bias. We considered that the risk of bias did not impact on the quality of evidence for liver-related mortality and adverse event outcomes, but it did for virological response. All trials compared peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin versus interferon plus ribavirin for participants with chronic hepatitis C. Three trials administered co-interventions (amantadine hydrochloride 200 mg daily to both intervention groups), and 24 trials were conducted without co-interventions. The effect observed between the two intervention groups regarding liver-related morbidity plus all-cause mortality (5/907 (0.55%) versus 4/882 (0.45%) was imprecise: OR 1.14 ( 95% CI 0.38 to 3.42; five trials; low quality of evidence), as was the risk of adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.68 to 1.09; 15 trials; low quality of evidence) or regarding adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.66 to 1.12; 17 trials; low quality of evidence). However, peginterferon plus ribavirin versus interferon plus ribavirin significantly increased the risk of neutropenia (332/2202 (15.1%) versus 117/1653 (7.1%); RR 2.15, 95% CI 1.76 to 2.61; 13 trials), thrombocytopenia (65/1113 (5.8%) versus 23/1082 (2.1%); RR 2.63, 95% CI 1.68 to 4.11; 10 trials), arthralgia (517/1740 (29.7%) versus 282/1194 (23.6%); RR 1.19, 95% CI 1.05 to 1.35; four trials), injection site reaction (627/1168 (53.7%) versus 186/649 (28.7%); RR 1.71, 95% CI 1.50 to 1.93; four trials), and nausea (606/1784 (34.0%) versus 354/1239 (28.6%); RR 1.13, 95% CI 1.01 to 1.26; four trials). The most frequent adverse event was fatigue, which occurred in 57% of participants (2024/3608). No significant difference was noted between peginterferon plus ribavirin versus interferon plus ribavirin in terms of fatigue (1177/2062 (57.1%) versus 847/1546 (54.8%); RR 1.01, 95% CI 0.96 to 1.07; 12 trials). No significant differences were reported between the two treatment groups regarding anaemia, headache, rigours, myalgia, pyrexia, weight loss, asthenia, depression, insomnia, irritability, alopecia, pruritus, skin rash, thyroid malfunction, decreased appetite, or diarrhoea. We were unable to identify any data on quality of life. Peginterferon plus ribavirin versus interferon plus ribavirin seemed to significantly increase the number of participants achieving sustained virological response (1673/3300 participants (50.7%) versus 1081/2804 patients (36.7%); RR 1.39, 95% CI 1.25 to 1.56; I2 = 64%; 27 trials; very low quality of evidence). However, the risk of bias in the 13/27 (48.1%) trials reporting on this outcome was high and was considered only 'lower' in the remainder. Because the conventional meta-analysis did not reach its required information size (n = 14,486 participants), we used trial sequential analysis to control for risks of random errors. Again, in this analysis, the estimated effect was statistically significant in favour of peginterferon. Subgroup analyses according to risk of bias, viral genotype, baseline viral load, past treatment history, and type of intervention yielded similarly significant results favouring peginterferon over interferon on the outcome of sustained virological response. AUTHORS' CONCLUSIONS: Peginterferon plus ribavirin versus interferon plus ribavirin seems to significantly increase the proportion of patients with sustained virological response, as well as the risk of certain adverse events. However, we have insufficient evidence to recommend or reject peginterferon plus ribavirin for liver-related morbidity plus all-cause mortality compared with interferon plus ribavirin. The clinical consequences of achieved sustained virological response are unknown, as sustained virological response is still an unvalidated surrogate outcome. We found no evidence of the potential benefits on quality of life in patients with achieved sustained virological response. Further high-quality research is likely to have an important impact on our confidence in the estimate of patient-relevant outcomes and is likely to change our estimates.There is very low quality evidence that peginterferon plus ribavirin increases the proportion of patients with sustained virological response in comparison with interferon plus ribavirin. There is evidence that it also increases the risk of certain adverse events.

The assessment of data mining for the prediction of therapeutic outcome in 3719 Egyptian patients with chronic hepatitis C.

INTRODUCTION: Decision-tree analysis; a core component of data mining analysis can build predictive models for the therapeutic outcome to antiviral therapy in chronic hepatitis C virus (HCV) patients. AIM: To develop a prediction model for the end virological response (ETR) to pegylated interferon PEG-IFN plus ribavirin (RBV) therapy in chronic HCV patients using routine clinical, laboratory, and histopathological data. PATIENTS AND METHODS: Retrospective initial data (19 attributes) from 3719 Egyptian patients with chronic HCV presumably genotype-4 was assigned to model building using the J48 decision tree-inducing algorithm (Weka implementation of C4.5). All patients received PEG-IFN plus RBV at Cairo-Fatemia Hospital, Cairo, Egypt in the context of the national treatment program. Factors predictive of ETR were explored and patients were classified into seven subgroups according to the different rates of ETR. The universality of the decision-tree model was subjected to a 10-fold cross-internal validation in addition to external validation using an independent dataset collected of 200 chronic HCV patients. RESULTS: At week 48, overall ETR was 54% according to intention to treat protocol. The decision-tree model included AFP level (<8.08 ng/ml) which was associated with high probability of ETR (73%) followed by stages of fibrosis and Hb levels according to the patients' gender followed by the age of patients. CONCLUSION: In a decision-tree model for the prediction for antiviral therapy in chronic HCV patients, AFP level was the initial split variable at a cutoff of 8.08 ng/ml. This model could represent a potential tool to identify patients' likelihood of response among difficult-to-treat presumably genotype-4 chronic HCV patients and could support clinical decisions regarding the proper selection of patients for therapy without imposing any additional costs.

Clinical, biochemical and pathological profiles of 5464 Egyptian chronic hepatitis C-infected patients.

BACKGROUND/AIMS: In Egypt, hepatitis C virus (HC is highly endemic with at least 91% are genotype-4. However, HCV-specific burden data for Egypt are scarce. The study aims to identify clinical, biochemical and pathological features of chronic HCV population in Egypt. METHODOLOGY: We analyzed retrospective data of 5,464 HCV-antibody and PCR positive patients attending pre-treatment assessment at one of the National Treatment Centers, Cairo, Egypt. RESULTS: Chronic HCV patients were males (81.4%) in their productive age, mean body mass index (BMI): 28 kg/m2. Laboratory profile demonstrated mean platelet count 214 x 10(3)/µ L with only 14% having thrombocytopenia, amino-transferases were mildly elevated: mean AST, ALT were 56 and 63 respectively,low viraemia: 50% had viral load <100 (x 10(3)) IU/mL,and median AFP level 3.3 ng/mL. Liver biopsy revealed ≤A2 in 92% of patients; 80% had ≤F2 and 7.3 % had F4 according to the METAVIR score. Meta regression demonstrated that advanced stages of fibrosis were significantly correlated with platelet count, AST/ALT ratio, AFP levels and BMI (p <0.001). However there was no correlation with viral load. CONCLUSIONS: To our knowledge, this is the first study on nationwide scale that provided the demographic, biochemical,and histological characteristics for this number of chronic HCV patients presumably genotype-4.

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, I(2), 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 I(2) 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 I(2) estimates. However, no previous studies have explored how many trials and events are required to ensure stable and reliable I(2) estimates, or how 95% CIs perform as evidence accumulates. METHODOLOGY/PRINCIPAL FINDINGS: To assess the stability and reliability of I(2) 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 I(2)--and monitored the I(2) estimates and their 95% CIs for each year of publication. In 10 of the 16 meta-analyses, the I(2) estimates fluctuated more than 40% over time. The median number of events and trials required before the cumulative I(2) estimates stayed within +/-20% of the final I(2) 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: I(2) estimates need to be interpreted with caution when the meta-analysis only includes a limited number of events or trials. Confidence intervals for I(2) estimates provide good coverage as evidence accumulates, and are thus valuable for reflecting the uncertainty associated with estimating I(2).

World Health Organization Guidelines: Use of cryotherapy for cervical intraepithelial neoplasia.

BACKGROUND: In 2008, cervical cancer was responsible for 275000 deaths, of which approximately 88% occurred in low- and middle-income countries. In 2009, the World Health Organization (WHO) committed to updating recommendations for use of cryotherapy for cervical intraepithelial neoplasia (CIN). METHODS AND RESULTS: We followed the WHO Handbook for Guidelines Development to develop present guidelines. An expert panel was established, which included clinicians, researchers, program directors, and methodologists. An independent group conducted systematic reviews and produced evidence summaries following the GRADE approach. GRADE evidence profiles were created for 16 key questions about the effects of cryotherapy in the presence of histologically confirmed CIN compared with no treatment and with loop electrosurgical excision procedure, as well as the use of different cryotherapy techniques. We identified a small number of randomized controlled trials or independently controlled observational studies. Surrogate outcomes were reported when evidence about outcomes critical to decision making were not available. The panel made 14 recommendations and documented factors that determined the strength and direction of the recommendations in decision tables. CONCLUSION: The present document summarizes new evidence-based WHO recommendations about the use of cryotherapy in women with histologically confirmed CIN for low-, middle-, and high-income countries.

Systematic review of influenza resistance to the neuraminidase inhibitors.

BACKGROUND: Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs), is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu®) and zanamivir (Relenza®); and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review.The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance. METHODS: We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms. RESULTS: We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%). The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral resistance among subjects given peramivir and was reported to be 0%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. Considerable heterogeneity between studies precluded definite inferences about subgroup results for immunocompromised patients, in-patients, and children. A meta-analysis of 4 studies reporting association between oseltamivir-resistance and pneumonia yielded a statistically significant risk ratio of 4.2 (95% CI 1.3 to 13.1, p = 0.02). Oseltamivir-resistance was not statistically significantly associated with other clinical complications and symptoms. CONCLUSION: Our results demonstrate that that a substantial number of patients may become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance may be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date.

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 © 2012 John Wiley & Sons, Ltd.

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

UNLABELLED: 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.

Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus.

BACKGROUND: Antiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV). OBJECTIVES: To assess the benefits and harms of antiviral treatment for chronic hepatitis C in patients with HIV. SEARCH STRATEGY: Trials were identified through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. The last search was May 2009. SELECTION CRITERIA: Randomised trials comparing at least 12 weeks of any anti-HCV treatment versus another treatment regimen or no treatment. Included patients had chronic hepatitis C and stable HIV irrespective of previous antiviral therapy. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of risk of bias were done in duplicate. Analysis was by intention-to-treat. MAIN RESULTS: Fourteen trials were included. None of the included 2269 patients were previously treated for chronic hepatitis C. Peginterferon (either 2a, 180 microgram, or 2b, 1.5 microgram/kg, once weekly) plus ribavirin was more effective in achieving end of treatment and sustained virological response compared with interferon plus ribavirin (5 trials, 1340 patients) or peginterferon (2 trials, 714 patients). The benefit of peginterferon plus ribavirin was seen irrespective of HCV genotype although patients with genotype 1 or 4 had lower response rates (27%) than patients with genotype 2 or 3 (56%). The remaining trials compared different treatment regimens in patients who were treatment naive or had no virological response after three months of treatment, but overall they had not enough power to show any effect of increasing the dose of interferon or adding both amantadine or ribavirin. The overall mortality was 23/2111 patients with no significant differences between treatment regimens. Treatment increased the risk of adverse events including anaemia and flu-like symptoms, and several serious adverse events occurred including fatal lactic acidosis, liver failure, and suicide due to depression. AUTHORS' CONCLUSIONS: Peginterferon plus ribavirin may be considered a treatment for patients with chronic hepatitis C and stable HIV who have not received treatment for hepatitis C as the intervention may clear the blood of HCV RNA. Supporting evidence comes mainly from the analysis of this non-validated surrogate outcome assessed in comparisons against other antiviral treatments. There is no evidence on treatment of patients who have relapsed or did not respond to previous therapy. Careful monitoring of adverse events is warranted.

Cryotherapy for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common primary malignant cancer of the liver. Evidence for the role of cryotherapy in the treatment of hepatocellular carcinoma is controversial. OBJECTIVES: The aim of this review is to evaluate the potential benefits and harms of cryotherapy for the treatment of hepatocellular carcinoma. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS until June 2009. We identified further studies by searching national and topic-specific databases, bibliographies, conference abstracts, journals, and grey literature. Furthermore, we reviewed the reference lists and contacted the principal authors of the identified studies. SELECTION CRITERIA: Randomised clinical trials (irrespective of language or publication status) comparing cryotherapy with or without co-intervention(s) to placebo, no treatment, or other control interventions were considered for the review. Due to the absence of randomised clinical trials, we searched for quasi-randomised studies as well as prospective cohort studies and retrospective cohort studies. DATA COLLECTION AND ANALYSIS: Two authors independently identified and assessed studies for their fulfilment of the inclusion criteria. Dichotomous data were expressed as risk ratio (RR) with 95% confidence intervals (CI). We performed the review following the recommendations of The Cochrane Collaboration. MAIN RESULTS: We were unable to identify any randomised clinical trials. We were also unable to identify quasi-randomised trials. Instead, we identified two prospective cohort studies and two retrospective cohort studies. However, only one of these studies could be included for the assessment of benefit as the study results were stratified according to both the type of hepatic malignancy (primary or secondary) and the intervention group. This retrospective study compared percutaneous cryotherapy with percutaneous radiofrequency. The remaining studies were excluded for the analyses of benefit but included for the assessment of harm. Both severe and non-severe adverse events were reported, but the true nature and extent of harm was difficult to asses. AUTHORS' CONCLUSIONS: At present, there is no evidence to recommend or refute cryotherapy for patients with hepatocellular carcinoma. Randomised clinical trials with low-risk of bias may help in defining the role of cryotherapy in the treatment of hepatocellular carcinoma.

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.