Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Inpatient Cost Assessment of Transjugular Intrahepatic Portosystemic Shunt in the USA from 2001 to 2012.

BACKGROUND: Despite widespread use of transjugular intrahepatic portosystemic shunt (TIPS) for treatment of portal hypertension, a paucity of nationwide data exists on predictors of the economic impact related to TIPS. AIMS: Using the National Inpatient Sample (NIS) database from 2001 to 2012, we aimed to evaluate factors contributing to hospital cost of patients admitted to US hospitals for TIPS. METHODS: Using the NIS, we identified a discharge-weighted national estimate of 61,004 TIPS procedures from 2001 to 2012. Through independent sample analysis, we determined profile factors related to increases in hospital costs. RESULTS: Of all TIPS cases, the mean charge adjusted for inflation to the year 2012 is $125,044 ± $160,115. The mean hospital cost adjusted for inflation is $44,901 ± $54,565. Comparing pre- and post-2005, mean charges and cost have increased considerably ($98,154 vs. $142,652, p < 0.001 and $41,656 vs. $46,453, p < 0.001, respectively). Patients transferred from a different hospital, weekend admissions, Asian/Pacific Islander patients, and hospitals in the Northeastern and Western region had higher cost. Number of diagnoses and number of procedures show positive correlations with hospital cost, with number of procedures exhibiting stronger relationships (Pearson 0.613). Comorbidity measures with highest increases in cost were pulmonary circulation disorders ($32,157 increase, p < 0.001). CONCLUSION: The cost of the TIPS procedure is gradually rising for hospitals. Alongside recent healthcare reform through the Affordable Care Act, measures to reduce the economic burden of TIPS are of increasing importance. Data from this study are intended to aid physicians and hospitals in identifying improvements that could reduce hospital costs.

Adherence, persistence, healthcare utilization, and cost benefits of guideline-recommended hepatitis B pharmacotherapy.

OBJECTIVE: To compare pharmacotherapy adherence, persistence, and healthcare utilization/costs among US patients with chronic hepatitis B (CHB) initiated on an oral antiviral monotherapy recommended as first-line treatment by current national (US) guidelines vs an oral antiviral not recommended as first-line monotherapy. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, patients aged 18-64 with medical claims for CHB who initiated an oral antiviral monotherapy for CHB between 07/01/05 and 01/31/10 were identified from a large US commercial health insurance claims database. Patients were continuously enrolled for a 6-month baseline period and ≥90 days follow-up. They were assigned to 'currently recommended first-line therapy' (RT: entecavir or tenofovir) or 'not currently recommended first-line therapy' (NRT: lamivudine, telbivudine, or adefovir) cohorts. MAIN OUTCOME MEASURES: Multivariate analyses were conducted to compare treatment adherence, persistence, healthcare utilization, and costs for RT vs NRT cohorts. RESULTS: Baseline characteristics were similar between RT (n=825) and NRT (n=916) cohorts. In multivariate analyses, RT patients were twice as likely as NRT patients to be adherent (OR=2.09; p<0.01) and persistent (mean: RT=361 days, NRT=298 days; p<0.01) and half as likely to have an inpatient stay (OR=0.527; p<0.01). Between the two oral antivirals recommended as first-line treatment, even though pharmacy cost was higher for entecavir, mean total healthcare costs for entecavir and tenofovir were similar ($1214 and $1332 per patient per month, respectively). Similar results were also observed with regard to adherence, persistence, and healthcare use for entecavir and tenofovir. CONCLUSIONS: A limitation associated with analysis of administrative claims data is that coding errors can be mitigated but are typically not fully eradicated by careful study design. Nevertheless, the current findings clearly indicate the benefits of initiating CHB treatment with an oral antiviral monotherapy recommended as first-line treatment by current guidelines.

Natural course, therapeutic options and economic evaluation of therapies for chronic hepatitis B.

Chronic hepatitis B virus infection afflicts 400 million people worldwide and untreated will progress to cirrhosis in 15-40% of individuals, with an associated increased risk for the development of hepatocellular carcinoma. The 'inactive carrier state' carries a benign prognosis with a very low risk of cirrhosis or hepatocellular carcinoma. However, the hepatitis B e antigen (HBeAg)-positive chronic hepatitis state is an active disease state with increased risk for progressing to cirrhosis and hepatocellular carcinoma. The HBeAg-negative mutant variety of chronic hepatitis B has been associated with a higher incidence of cirrhosis at initial presentation and more frequent progression to hepatocellular carcinoma compared with the wild-type hepatitis B. Five medications are currently approved by the US FDA for the treatment of chronic hepatitis B: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir and peginterferon-alpha-2a. Interferon-alpha therapy has been shown to increase the rate of HBeAg and hepatitis B DNA loss with a small chance of hepatitis B surface antigen loss, but has significant adverse effects and is ineffective against the HBeAg-negative mutant. Lamivudine is a safely used, orally administered drug with good efficacy, but is associated with the development of a lamivudine-resistant (Lam-R) mutant in a large proportion of patients after long-term therapy. High relapse rates after lamivudine therapy make this medication less effective in the HBeAg-negative mutant also. Adefovir dipivoxil is a safely used, orally administered drug, which is effective against the Lam-R mutant. Adefovir dipivoxil is effective against the wild-type and HBeAg-negative hepatitis B and has a very low incidence of resistance development. Entecavir is a highly potent and selective new oral drug against hepatitis B. It has demonstrated no resistance development in treatment-naive patients, but a low incidence of resistance in patients infected with prior Lam-R mutants. Peginterferon-alpha-2a is administered once weekly and has improved efficacy compared with standard interferon-alpha and lamivudine. However, it has a similar adverse-effect profile to standard interferon-alpha. Pharmacoeconomic studies have demonstrated a cost benefit in treating chronic hepatitis B patients compared with no therapy. However, results have been conflicting, with earlier studies showing a cost advantage of lamivudine over interferon-alpha and a more recent, comprehensive study favouring interferon-alpha monotherapy in HBeAg-negative patients and adefovir dipivoxil 'salvage' after lamivudine resistance development in HBeAg-positive patients.

Conversion from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine is safe and cost-effective in patients receiving long-term prophylaxis to prevent hepatitis B recurrence after liver transplantation.

Recurrent hepatitis B infection after liver transplantation was previously frequent and associated with significant allograft failure and mortality. Recurrence rates of hepatitis B were improved with the use of passive immunoprophylaxis with hepatitis B immune globulin, and later, lamivudine monotherapy. Combination prophylaxis with intravenous hepatitis B immune globulin and lamivudine substantially decreased rates of hepatitis B recurrence, but intravenous administration of hepatitis B immune globulin was expensive and associated with significant adverse effects. In the current study, 59 patients receiving primary liver transplantation for chronic hepatitis B infection were prospectively followed up after converting from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine. All patients tolerated intramuscular hepatitis B immune globulin well. At a median follow-up of 511 days after conversion to intramuscular hepatitis B immune globulin, 58 of 59 patients (98.3%) were hepatitis B surface antigen-negative. Twenty-one patients (35.6%) required a median of one supplemental intravenous hepatitis B immune globulin infusion to maintain therapeutic antibody levels. Economic analysis showed an average cost-effectiveness ratio for combination intramuscular hepatitis B immune globulin plus lamivudine of $52,600 per recurrence prevented, which was far below the cost of lamivudine monotherapy and of intravenous hepatitis B immune globulin alone or in combination with lamivudine. These results suggest that intramuscular administration of hepatitis B immune globulin in combination with lamivudine offers a safe, effective, and cost-effective approach to preventing hepatitis B recurrence after orthotopic liver transplantation.

Comparison of the cost and effectiveness of two strategies for maintaining hepatitis B immunity in hemodialysis patients.

A decision-analysis model was developed to compare the strategies to maintain hepatitis B virus (HBV) immunity in hemodialysis patients who responded to the primary HBV vaccine. Our hypothesis is that the routine, annual administration of the vaccine booster to all hemodialysis patients (non-screening strategy) is more cost-effective than the current strategy of vaccination based on anti-HBs titers (screening strategy). Under baseline assumptions, the screening strategy was less costly and was associated with fewer HBV infections than the non-screening strategy. The results of our model did not support our hypothesis, and indicate that regularly screening patients for HBV immunity before revaccination is less costly and more effective than the empiric vaccination of hemodialysis patients.