Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy.

BACKGROUND: Although studies suggest decreased incident hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA), data are conflicting regarding HCC recurrence and aggressiveness in patients who have a history of HCC with complete response. AIM: Characterize HCC recurrence patterns after DAA therapy. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 2015 to December 2017 and identified studies evaluating HCC recurrence patterns following DAA therapy. A pooled estimate was calculated using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with PRISMA guidelines. RESULTS: Among 24 studies (n = 1820 patients), the proportion of patients with HCC recurrence following DAA therapy ranged from 0% to 59% (pooled estimate 24.4%; 95% CI: 18.4%-30.4%). Among 11 full text manuscripts, pooled HCC recurrence was 21.9% (95% CI: 16.2%-28.3%). Factors associated with recurrence included history of prior HCC recurrence and a shorter interval between HCC complete response and DAA initiation. Nine studies comparing DAA-treated and interferon-treated or untreated patients found similar recurrence among DAA-treated patients. Most (77.8%) patients with HCC recurrence were detected at an early tumour stage, of whom 64.7% received curative treatment. Study limitations included heterogeneous cohorts, potential misclassification of HCC absence prior to DAA, ascertainment bias for recurrence, and short durations of follow-up. CONCLUSIONS: Current data suggest acceptable HCC recurrence rates after DAA therapy, particularly if DAA therapy is delayed at least 6 months after HCC complete response. However, data characterising HCC recurrence after DAA therapy are of limited quality, highlighting the need for high quality prospective studies.

Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.

BACKGROUND: Abdominal ultrasound fails to detect over one-fourth of hepatocellular carcinoma (HCC) at an early stage in patients with cirrhosis. Identifying patients in whom ultrasound is of inadequate quality can inform interventions to improve surveillance effectiveness. AIM: To evaluate and identify predictors of ultrasound quality in patients with cirrhosis. METHODS: We performed a retrospective cohort study among patients who underwent ultrasound examination for a cirrhosis-related indication between April 2015 and October 2015. Three fellowship-trained abdominal radiologists collectively reviewed all ultrasound exams and categorised exam quality as definitely adequate, likely adequate, likely inadequate and definitely inadequate to exclude liver lesions. We performed multivariable logistic regression to determine characteristics associated with inadequate ultrasound quality. RESULTS: Among 941 patients, 191 (20.3%) ultrasounds were inadequate for excluding HCC- 134 definitely inadequate and 57 likely inadequate. In multivariable analysis, inadequate quality was associated with male gender (OR 1.68, 95% CI 1.14-2.48), body mass index category (OR 1.67, 95% CI 1.45-1.93), Child-Pugh B or C cirrhosis (OR 1.93, 95% CI 1.32-2.81), alcohol-related cirrhosis (OR 2.11, 95% CI 1.33-3.37), NASH cirrhosis (OR 2.87, 95% CI 1.71-4.80), and in-patient status (OR 1.55, 95% CI 1.01-2.37). Ultrasounds were inadequate in over one-third of patients with Child-Pugh C cirrhosis, BMI >35, or NASH cirrhosis. CONCLUSIONS: One in five ultrasounds in patients with cirrhosis are inadequate for exclusion of HCC, which can contribute to surveillance failure. Alternative surveillance modalities are needed in subgroups prone to inadequate ultrasounds including obese patients, those with Child Pugh B or C cirrhosis, and those with alcohol- or NASH-related cirrhosis.

Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease.

BACKGROUND: Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD. METHODS: After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17-2.36 and RR: 1.43, 95% CI: 1.17-1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51-2.09 and RR: 1.68, 95% CI: 1.46-1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21-7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients. CONCLUSIONS: All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.

Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.

BACKGROUND: Antibodies against tumour necrosis factor-alpha (anti-TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF agents in UC. METHODS: After screening 506 studies, reviewers extracted information on seven studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72-3.47 and RR: 1.65, 95% CI: 1.37-1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52-2.62 and RR: 1.76, 95% CI: 1.46-2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively. CONCLUSIONS: This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta-analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti-TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.

Meta-analysis: underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States.

BACKGROUND: Despite wide availability of treatment options for hepatocellular carcinoma (HCC), several studies have suggested underutilisation in clinical practice. AIMS: To quantify utilisation rates for HCC treatment among patients with HCC in the United States, and to summarise patterns of association between utilisation rates and patient socio-demographic characteristics. METHODS: We performed a systematic literature review using the Medline database from January 1989 to March 2013. Two investigators independently extracted data on patient populations, study methods and results using standardised forms. Pooled treatment rates for any treatment and curative treatment, with 95% confidence intervals, were calculated. Prespecified subgroup analysis was performed to identify patient-level correlates of treatment utilisation. RESULTS: We identified 24 studies that met inclusion criteria. The pooled rates of any treatment and curative treatment were 52.8% (95% CI 52.2-53.4%) and 21.8% (95% CI 21.4-22.1%) respectively. Among patients diagnosed at an early stage, the pooled curative treatment rate was 59.0% (95% CI 58.1-59.9%). Elderly, non-Caucasians and patients of low socioeconomic status had lower treatment rates than their counterparts. CONCLUSIONS: Rates of HCC treatment in the United States, including curative treatment rates among patients detected at an early stage, are disappointingly low. Future efforts should focus on identifying appropriate intervention targets to increase treatment rates and reduce socio-demographic disparities.

Use of the AST to platelet ratio index in HCV/HIV co-infected patients.

BACKGROUND: The AST to platelet ratio index (APRI), a non-invasive marker of liver fibrosis, has not been well studied in HCV/HIV (hepatitis C virus/human immunodeficiency virus) co-infected patients with advanced HIV. AIM: To compare the accuracy of APRI in HCV/HIV co-infected patients to that in HCV mono-infected patients and to determine the impact of CD4+ T-cell counts on its performance. METHODS: We identified 106 consecutive HCV/HIV co-infected patients and 105 matched HCV mono-infected patients who underwent liver biopsy at Harborview Medical Center over a 5-year period. Performance characteristics were calculated and receiver operating characteristic (ROC) analysis conducted. RESULTS: The area under the ROC curve (AUROC) of APRI for predicting significant fibrosis was similar when comparing those with and without HIV co-infection (0.77 vs. 0.86, P = 0.18), but was lower in HIV co-infected patients with CD4 counts <250 cells/mm³ (0.64 vs. 0.86, P = 0.05). In HIV co-infected patients with CD4 counts ≥250, APRI had higher negative predictive value (93% vs. 88%, P = 0.57), positive predictive value (63% vs. 40%, P = 0.43) and specificity (95% vs. 88%, P = 0.05) than in those with lower CD4 counts. CONCLUSIONS: The AST to platelet ratio index (APRI) performance characteristics appear to be suboptimal in HCV/HIV co-infected patients with CD4 counts <250 and they require further study in this population at increased risk for advanced liver disease.

Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease generally has a benign course; however, patients with non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Currently, there is a lack of consensus about optimal NASH treatment. AIM: To assess the efficacy of insulin-sensitizing agents on histological and biochemical outcomes in randomized control trials of biopsy-proven NASH. METHODS: Multiple online databases and conference abstracts were searched. Random effects meta-analyses were performed, with assessment for heterogeneity and publication bias. RESULTS: Nine trials were included; five trials using thiazolidinediones (glitazones), three using metformin and one trial using both drugs. There was no publication bias. Compared with controls, glitazones resulted in improved steatosis (WMD = 0.57, 95% CI 0.36-0.77, P = <0.001), hepatocyte ballooning (WMD = 0.36, 95% CI 0.24-0.49, P < 0.001) and ALT (WMD = 16.4, 95% CI 7.7-25.0, P < 0.001), but not inflammation (P = 0.09) or fibrosis (P = 0.11). In patients without diabetes, glitazones significantly improved all histological and biochemical outcomes, most importantly including fibrosis (WMD = 0.29, 95% CI 0.078-0.51, P = 0.008). Metformin failed to improve any pooled outcome. CONCLUSIONS: Treatment of NASH with glitazones, but not metformin, demonstrates a significant histological and biochemical benefit, especially in patients without diabetes. Additional studies are needed to investigate long-term outcomes of glitazone therapy in patients without diabetes.

Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy.

BACKGROUND: The efficacy of re-treating genotype I hepatitis C virus (HCV) patients who failed combination therapy with interferon/pegylated interferon (PEG-IFN) and ribavirin remains unclear. AIMS: To quantify sustained virological response (SVR) rates with different re-treatment regimens through meta-analysis of randomized controlled trials (RCTs). METHODS: Randomized controlled trials of genotype I HCV treatment failure patients that compared currently available re-treatment regimens were selected. Two investigators independently extracted data on patient population, methods and results. The pooled relative risk of SVR for treatment regimens was computed using a random effects model. RESULTS: Eighteen RCTs were included. In nonresponders to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN combination therapy improved SVR compared with standard PEG-IFN combination therapy (RR=1.49; 95% CI: 1.09-2.04), but SVR rates did not exceed 18% in most studies. In relapsers to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN or prolonged CIFN improved SVR (RR=1.57; 95% CI: 1.16-2.14) and achieved SVR rates of 43-69%. CONCLUSIONS: In genotype I HCV treatment failure patients who received combination therapy, re-treatment with high-dose PEG-IFN combination therapy is superior to re-treatment with standard combination therapy, although SVR rates are variable for nonresponders (≤18%) and relapsers (43-69%). Re-treatment may be appropriate for select patients, especially relapsers and individuals with bridging fibrosis or compensated cirrhosis.

The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre.

BACKGROUND: The incidence of cholangiocarcinoma is rising. Accurate predictors of survival at diagnosis are not well defined. AIM: To clarify the clinical presentation and prognostic factors of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in a contemporary cohort of patients. METHODS: Records for consecutive patients at the University of Michigan hospital diagnosed with cholangiocarcinoma between January 2003 and April 2008 were reviewed. RESULTS: In all, 136 patients had cholangiocarcinoma (79 intra- and 57 extrahepatic cholangiocarcinoma). Median survival was 27.3 months-25.8 months for intrahepatic cholangiocarcinoma and 30.3 months for extrahepatic cholangiocarcinoma. Independent predictors of mortality at presentation on multivariate analysis were elevated bilirubin level (HR 1.04, 95%CI 1.01-1.07), CA 19-9 levels >100 U/mL (HR 1.90, 95%CI 1.17-3.08) and stage of disease (HR 1.51, 95%CI 1.16-1.96). After adjusting for baseline prognostic factors, surgical therapy was associated with improved survival (HR 0.48; 95% CI 0.26-0.88). There were no significant differences regarding clinical presentation, disease stage (P = 0.98), and survival (P = 0.51) between intra- and extrahepatic cholangiocarcinoma. CONCLUSIONS: Survival for cholangiocarcinoma remains poor with no significant difference in outcomes between intra- and extrahepatic cholangiocarcinoma. Stage of disease, bilirubin level and CA 19-9 level are important prognostic factors at presentation. Surgical therapy provides similar efficacy for both tumours when adjusted for other prognostic variables.