Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus

We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE), based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma (EAC). Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve (AUC)=0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals, who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 minutes. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE

Demographic characteristics of patients randomized to boceprevir and telaprevir.

<p>Demographic characteristics of patients randomized to boceprevir and telaprevir.</p

Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C

<div><p>Background</p><p>Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options.</p><p>Methods</p><p>We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved.</p><p>Results</p><p>Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs.$57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial.</p><p>Conclusion</p><p>Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).</p></div

Resource use associated with boceprevir and telaprevir.

<p>Resource use associated with boceprevir and telaprevir.</p

Demographic characteristics of patients randomized to boceprevir and telaprevir.

<p>Demographic characteristics of patients randomized to boceprevir and telaprevir.</p

SVR24 rates based on treatment exposure to boceprevir and telaprevir.

<p>SVR24 rates based on treatment exposure to boceprevir and telaprevir.</p

CONSORT Flow Diagram.

<p>CONSORT Flow Diagram.</p