Data are available such that choice of Helicobacter pylori therapy for an individual patient can be reliably predicted. Here, treatment success is defined as a cure rate of 90% or greater. Treatment ...outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with the knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). We provide the formula for predicting outcome and we illustrate the calculations. Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete; neither should continue to be used as empiric therapies (ie, 7- and 14-day triple therapies fail when clarithromycin resistance exceeds 5% and 15%, respectively, and 10-day sequential therapy fails when metronidazole resistance exceeds 20%). Therapy should be individualized based on prior history and whether the patient is in a high-risk group for resistance. The preferred choices for Western countries are 14-day concomitant therapy, 14-day bismuth quadruple therapy, and 14-day hybrid sequential-concomitant therapy. We also provide details regarding the successful use of fluoroquinolone-, rifabutin-, and furazolidone-containing therapies. Finally, we provide recommendations for the efficient development (ie, identification and optimization) of new regimens, as well as how to prevent or minimize failures. The trial-and-error approach for identifying and testing regimens frequently resulted in poor treatment success. The described approach allows outcome to be predicted and should simplify treatment and drug development.
Background & Aims Eradication of Helicobacter pylori infection has been reported to reduce the risk of gastric cancer among asymptomatic individuals in high-risk areas. The magnitude of benefit of H ...pylori eradication in populations with different levels of gastric cancer risk and in different clinical scenarios is unclear. We performed a systematic review and meta-analysis of randomized controlled trials and observational studies to investigate the effects of H pylori eradication on the incidence of gastric cancer. Methods We searched PubMed, Cochrane Library, and ClinicalTrials.gov , reviewing titles and abstracts of studies of the effects of eradication of H pylori infection on risk of gastric cancer, through May 2015. We also searched bibliographies of included studies, related reviews, and abstracts presented at Digestive Disease Week. Twenty-four eligible studies (22 research manuscripts and 2 abstracts) were included in our meta-analysis (715 incident gastric cancers among a total of 48,064 individuals/340,255 person-years). We assessed the effects, as well as their modification by baseline gastric cancer incidence, study design (randomized trial vs observational study), clinical scenario (asymptomatic infected individuals vs individuals after endoscopic resection of early gastric cancer), demographic characteristics of patients (age and sex), and duration of follow-up. Results After adjustment for baseline gastric cancer incidence, individuals with eradication of H pylori infection had a lower incidence of gastric cancer than those who did not receive eradication therapy (pooled incidence rate ratio = 0.53; 95% confidence interval: 0.44−0.64). There was little heterogeneity among studies. Baseline gastric cancer incidence modified the benefit of H pylori eradication ( P = .037 for interaction); the incidence rate ratio of gastric cancer decreased in a nonlinear fashion with increasing baseline incidence of gastric cancer ( P = .018, in comparison with the linear model). The benefit also modestly increased with age ( P = .023 for interaction), but this might be due to correlation between age and baseline gastric cancer incidence. Eradication provided significant benefit for asymptomatic infected individuals (pooled incidence rate ratio, 0.62; 95% CI: 0.49−0.79) and individuals after endoscopic resection of gastric cancers (pooled incidence rate ratio, 0.46; 95% CI: 0.35−0.60). The benefits of H pylori eradication did not differ with study design, sex, or follow-up period. Conclusions In a systematic review and meta-analysis, we associated eradication of H pylori infection with a reduced incidence of gastric cancer. The benefits of eradication vary with baseline gastric cancer incidence, but apply to all levels of baseline risk.
Tumor recurrence is a major issue for patients with hepatocellular carcinoma (HCC) following curative liver resection.
To investigate the association between nucleoside analogue use and risk of tumor ...recurrence in patients with hepatitis B virus (HBV)--related HCC after curative surgery.
A nationwide cohort study between October 2003 and September 2010. Data from the Taiwan National Health Insurance Research Database. Among 100 938 newly diagnosed HCC patients, we identified 4569 HBV-related HCC patients who received curative liver resection for HCC between October 2003 and September 2010.
The risk of first tumor recurrence was compared between patients not taking nucleoside analogues (untreated cohort, n = 4051) and patients taking nucleoside analogues (treated cohort, n = 518). Cumulative incidences and hazard ratios (HRs) were calculated after adjusting for competing mortality.
The treated cohort had a higher prevalence of liver cirrhosis when compared with the untreated cohort (48.6% vs 38.7%; P < .001), but lower risk of HCC recurrence (n = 106 20.5% vs n = 1765 43.6%; P < .001), and lower overall death (n = 55 10.6% vs n = 1145 28.3%; P < .001). After adjusting for competing mortality, the treated cohort had a significantly lower 6-year HCC recurrence rate (45.6%; 95% CI, 36.5%-54.6% vs untreated, 54.6%; 95% CI, 52.5%-56.6%; P < .001). Six-year overall mortalities for treated cohorts were 29.0% (95% CI, 20.0%-38.0%) and for untreated 42.4% (95% CI, 40.0%-44.7%; P < .001). On modified Cox regression analysis, nucleoside analogue use (HR, 0.67; 95% CI, 0.55-0.81; P < .001), statin use (HR, 0.68; 95% CI, 0.53-0.87; P = .002), and nonsteroidal anti-inflammatory drugs or aspirin use (HR, 0.80; 95% CI, 0.73-0.88; P < .001) were independently associated with a reduced risk of HCC recurrence. Multivariable stratified analyses verified the association in all subgroups of patients, including those who were noncirrhotic (HR, 0.56; 95% CI, 0.42-0.76) and diabetic (HR, 0.52; 95% CI, 0.31-0.89).
Nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection.
Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in ...different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow-up duration of 6.32 years in the study cohort, the 10-year cumulative incidence of HCC was 2.73% 95% confidence interval (CI): 1.69-3.76%. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk hazard ratio (HR) 6.80, 95% CI: 3.00-15.42; p < 0.001. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05-1.11) and statin use (HR 0.29, 95% CI: 0.12-0.68) were also identified as independent risk factors. The 10-year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99-18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0-1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.
Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut ...microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD.
Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls.
Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 95% confidence interval 0.474 to 0.758, P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 95% CI: 0.102-0.887, P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 95% CI - 0.043-0.852, P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03).
This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.
Summary Background Major adjuvant treatments for pancreatic adenocarcinoma include fluorouracil, gemcitabine, chemoradiation, and chemoradiation plus fluorouracil or gemcitabine. Since the optimum ...regimen remains inconclusive, we aimed to compare these treatments in terms of overall survival after tumour resection and in terms of grade 3–4 toxic effects with a systematic review and random-effects Bayesian network meta-analysis. Methods We searched PubMed, trial registries, and related reviews and abstracts for randomised controlled trials comparing the above five treatments with each other or observation alone before April 30, 2013. We estimated relative hazard ratios (HRs) for death and relative odds ratios (ORs) for toxic effects among different therapies by combining HRs for death and survival durations and ORs for toxic effects of included trials. We assessed the effects of prognostic factors on survival benefits of adjuvant therapies with meta-regression. Findings Ten eligible articles reporting nine trials were included. Compared with observation, the HRs for death were 0·62 (95% credible interval 0·42–0·88) for fluorouracil, 0·68 (0·44–1·07) for gemcitabine, 0·91 (0·55–1·46) for chemoradiation, 0·54 (0·15–1·80) for chemoradiation plus fluorouracil, and 0·44 (0·10–1·81) for chemoradiation plus gemcitabine. The proportion of patients with positive lymph nodes was inversely associated with the survival benefit of adjuvant treatments. After adjustment for this factor, fluorouracil (HR 0·65, 0·49–0·84) and gemcitabine (0·59, 0·41–0·83) improved survival compared with observation, whereas chemoradiation resulted in worse survival than fluorouracil (1·69, 1·12–2·54) or gemcitabine (1·86, 1·04–3·23). Chemoradiation plus gemcitabine was ranked the most toxic, with significantly higher haematological toxic effects than second-ranked chemoradiation plus fluorouracil (OR 13·33, 1·01–169·36). Interpretation Chemotherapy with fluorouracil or gemcitabine is the optimum adjuvant treatment for pancreatic adenocarcinoma and reduces mortality after surgery by about a third. Chemoradiation plus chemotherapy is less effective in prolonging survival and is more toxic than chemotherapy. Funding None.
The rising prevalence of antibiotic resistance and the long‐term safety following eradication therapy are important issues in the management of Helicobacter pylori infection. The prevalence of ...clarithromycin, levofloxacin, and metronidazole resistance of H. pylori has increased to 21%, 27%, and 45%, respectively, in the Asia‐Pacific region. Personalized treatment guided by susceptibility testing may provide a reliably excellent eradication rate in the first‐line treatment but is costly and not widely available. Population‐specific empirical therapy according to the local prevalence of antibiotic resistance may be an alternative strategy. Levofloxacin‐based therapy and bismuth quadruple therapy are the recommended second‐line rescue therapy. Susceptibility testing or genotypic resistance‐guided therapy is the preferred treatment for refractory H. pylori infection, but empirical therapy may be an acceptable alternative. Eradication of H. pylori leads to short‐term perturbation of gut microbiota. The diversity of gut microbiota can be restored months after eradication therapy, but the speed of recovery varies with regimens. The short‐term increases of antibiotic resistance of Escherichia coli and Klebsiella pneumoniae may be restored to basal states months after H. pylori eradication. Future studies that apply in‐depth sequencing, such as shotgun metagenomics sequencing, are needed to clarify whether the compositions of gut microbiota at the species level are fully restored.
Summary
Background
There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB).
Aim
To investigate if ...hepatitis B core‐related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation.
Methods
This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score.
Results
During a median follow‐up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5‐year cumulative incidence of 56.1% (95% CI 46.7‐66.0%) and 8.8% (95% CI 4.3‐17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE‐B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low‐risk patients predicted by the score.
Conclusions
Serum HBcrAg and HBsAg levels were independent predictors of off‐NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB.
Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population‐based cohort study aimed to investigate whether antiviral therapy for HCV ...infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8‐year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval CI, 0.3‐2.0%), 9.3% (95% CI, 5.9‐12.7%), and 3.3% (95% CI, 2.3‐4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1‐5.0%), 5.3% (95% CI, 3.0‐7.5%), and 6.1% (95% CI, 4.8‐7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1‐6.1%), 6.6% (95% CI, 3.7‐9.5%), and 7.4% (95% CI, 5.9‐9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate‐adjusted hazard ratios of 0.16 (95% CI, 0.07‐0.33%) for ESRD, 0.53 (95% CI, 0.30‐0.93) for ischemic stroke, and 0.64 (95% CI, 0.39‐1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (Hepatology 2014;59:1293‐1302)
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