Colonoscopy and Colorectal Cancer Mortality in the Veterans Affairs Health Care System: A Case–Control Study: Annals of Internal Medicine: Vol 168, No 7

Background: Colonoscopy is widely used in the Veterans Affairs (VA) health care system for colorectal cancer (CRC) prevention, but its effect on CRC mortality is unknown. Objective: To determine whether colonoscopy is associated with decreased CRC mortality in veterans and whether its effect differs by anatomical location of CRC. Design: Case–control study. Setting: VA–Medicare administrative data. Participants: Case patients were veterans aged 52 years or older who were diagnosed with CRC between 2002 and 2008 and died of the disease by the end of 2010. Case patients were matched to 4 control patients without prior CRC on the basis of age, sex, and facility. Conditional logistic regression was performed to calculate odds ratios (ORs) for exposure to colonoscopy, with adjustment for race, Charlson Comorbidity Index score, selected chronic conditions, nonsteroidal anti-inflammatory drug use, and family history of CRC. Measurements: Exposure to colonoscopy was determined from 1997 to 6 months before CRC diagnosis in case patients and to a corresponding date in control patients. Subgroup analysis was performed for patients who had undergone screening colonoscopy. Results: A total of 4964 case patients and 19 856 control patients were identified. Case patients were significantly less likely to have undergone any colonoscopy (OR, 0.39 [95% CI, 0.35 to 0.43]). Colonoscopy was associated with reduced mortality for left-sided cancer (OR, 0.28 [CI, 0.24 to 0.32]) and right-sided cancer (OR, 0.54 [CI, 0.47 to 0.63]). The results were similar for patients who had undergone screening colonoscopy (overall OR, 0.30 [CI, 0.24 to 0.38]). Sensitivity analyses that varied the interval between CRC diagnosis and colonoscopy exposure did not affect the primary findings. Limitation: Unmeasured confounding. Conclusion: In this study using national VA–Medicare data, colonoscopy was associated with significant reductions in CRC mortality among veterans and was associated with greater benefit for left-sided cancer than right-sided cancer. Primary Funding Source: U.S. Department of Veterans Affairs.

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System

Background: Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV–HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. Objective: To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. Design: Descriptive case series. Setting: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Patients: 29 patients with HBV-R receiving HCV DAAs. Measurements: Clinical and laboratory data. Results: The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. Limitations: The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. Conclusion: Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV–HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection. Primary Funding Source: None.

Presence of Human Hepegivirus-1 in a Cohort of People Who Inject Drugs

Background: Next-generation metagenomic sequencing (NGMS) has opened new frontiers in microbial discovery but has been clinically characterized in only a few settings. Objective: To explore the plasma virome of persons who inject drugs and to characterize the sensitivity and accuracy of NGMS compared with quantitative clinical standards. Design: Longitudinal and cross-sectional studies. Setting: A clinical trial (ClinicalTrials.gov: NCT01285050) and a well-characterized cohort study of persons who have injected drugs. Participants: Persons co-infected with hepatitis C virus (HCV) and HIV. Measurements: Viral nucleic acid in plasma by NGMS and quantitative polymerase chain reaction (PCR). Results: Next-generation metagenomic sequencing generated a total of 600 million reads, which included the expected HIV and HCV RNA sequences. HIV and HCV reads were consistently identified only when samples contained more than 10 000 copies/mL or IU/mL, respectively, as determined by quantitative PCR. A novel RNA virus, human hepegivirus-1 (HHpgV-1), was also detected by NGMS in 4 samples from 2 persons in the clinical trial. Through use of a quantitative PCR assay for HHpgV-1, infection was also detected in 17 (10.9%) of 156 members of a cohort of persons who injected drugs. In these persons, HHpgV-1 viremia persisted for a median of at least 4538 days and was associated with detection of other bloodborne viruses, such as HCV RNA and SEN virus D. Limitation: The medical importance of HHpgV-1 infection is unknown. Conclusion: Although NGMS is insensitive for detection of viruses with relatively low plasma nucleic acid concentrations, it may have broad potential for discovery of new viral infections of possible medical importance, such as HHpgV-1. Primary Funding Source: National Institutes of Health.

Screening for Colorectal Cancer With Fecal Immunochemical Testing With and Without Postpolypectomy Surveillance Colonoscopy: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 167, No 8

Background: Population-based screening to prevent colorectal cancer (CRC) death is effective, but the effectiveness of postpolypectomy surveillance is unclear. Objective: To evaluate the additional benefit in terms of cost-effectiveness of colonoscopy surveillance in a screening setting. Design: Microsimulation using the ASCCA (Adenoma and Serrated pathway to Colorectal CAncer) model. Data Sources: Dutch CRC screening program and published literature. Target Population: Asymptomatic persons aged 55 to 75 years without a prior CRC diagnosis. Time Horizon: Lifetime. Perspective: Health care payer. Intervention: Fecal immunochemical test (FIT) screening with colonoscopy surveillance performed according to the Dutch guideline was simulated. The comparator was no screening or surveillance. FIT screening without colonoscopy surveillance and the effect of extending surveillance intervals were also evaluated. Outcome Measures: CRC burden, colonoscopy demand, life-years, and costs. Results of Base-Case Analysis: FIT screening without surveillance reduced CRC mortality by 50.4% compared with no screening or surveillance. Adding surveillance to FIT screening reduced mortality by an additional 1.7% to 52.1% but increased lifetime colonoscopy demand by 62% (from 335 to 543 colonoscopies per 1000 persons) at an additional cost of €68 000, for an increase of 0.9 life-year. Extending the surveillance intervals to 5 years reduced CRC mortality by 51.8% and increased colonoscopy demand by 42.7% compared with FIT screening without surveillance. In an incremental analysis, incremental cost-effectiveness ratios (ICERs) for screening plus surveillance exceeded the Dutch willingness-to-pay threshold of €36 602 per life-year gained. Results of Sensitivity Analysis: When using a parameter set representing low colorectal lesion prevalence or when colonoscopy costs were halved or colorectal lesion incidence was doubled, screening plus surveillance became cost-effective compared with screening without surveillance. Limitation: Limited data on FIT performance and background CRC risk in the surveillance population. Conclusion: Adding surveillance to FIT screening is not cost-effective based on the Dutch ICER threshold and substantially increases colonoscopy demand. Extending surveillance intervals to 5 years would decrease colonoscopy demand without substantial loss of effectiveness. Primary Funding Source: Alpe d'HuZes, Dutch Cancer Society, and Stand Up To Cancer.

Methods and Reporting Studies Assessing Fecal Microbiota Transplantation: A Systematic Review: Annals of Internal Medicine: Vol 167, No 1

Background: Fecal microbiota transplantation (FMT) could be a novel treatment option for several chronic diseases associated with altered gut microbiota. Purpose: To examine the conduct and reporting of studies assessing FMT. Data Sources: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science from inception to 31 January 2017. Study Selection: Two reviewers independently examined titles and abstracts to identify all English-language reports of human clinical studies assessing the safety or efficacy of FMT. Data Extraction: Three reviewers independently assessed study types and characteristics and the reporting of important methodological components of the FMT intervention. Data Synthesis: Most (84%) of the 85 published reports found addressed the use of FMTs for Clostridium difficile infection or inflammatory bowel disease, and most (87%) were non–randomized controlled trials. Important methodological components that were not reported in published studies included the following: eligibility criteria for donors (47%), materials used for collecting stools and the period of collection (96%), methods used for conservation of stools (76%), the amount and type of stools used (for example, fresh or frozen), and duration of stool conservation (67%). Many (58%) did not report an analysis of microbiota composition. Limitations: Lack of universal consensus regarding the most important methodological components of FMT and inability to assess the actual conduct of studies and whether the publication process affected the completeness of reporting. Conclusion: Key components of FMT interventions, which are necessary to replicate and understand study findings about efficacy and safety, are poorly reported. Primary Funding Source: No specific funding.

Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: A Cohort Study: Annals of Internal Medicine: Vol 167, No 3

Background: Clostridium difficile infection (CDI), the most common health care–associated infection, often recurs. Fecal microbiota transplantation is increasingly used to treat multiply recurrent CDI (mrCDI). Objective: To determine whether the incidence of mrCDI is increasing in proportion to CDI and to identify risk factors for mrCDI. Design: Retrospective cohort study. Setting: United States. Participants: 38 911 718 commercially insured patients in the OptumInsight Clinformatics Database, of whom 45 341 developed CDI. Measurements: Age- and sex-standardized incidence rates for CDI and mrCDI. Results: From 2001 to 2012, the annual incidence of CDI and mrCDI per 1000 person-years increased by 42.7% (from 0.4408 to 0.6289 case) and 188.8% (from 0.0107 to 0.0309 case), respectively. The increase in mrCDI incidence was independent of known risk factors for CDI. Those who developed mrCDI were older (median age, 56.0 vs. 49.0 years; adjusted odds ratio [aOR] per 10-year increase in age, 1.25 [95% CI, 1.21 to 1.29]) and were more likely to be female (63.8% vs. 58.7%; aOR, 1.24 [CI, 1.11 to 1.38]) and to have used antibiotics (72.3% vs. 58.8%; aOR, 1.79 [CI, 1.59 to 2.01]), proton-pump inhibitors (24.6% vs. 18.2%; aOR, 1.14 [CI, 1.01 to 1.29]), or corticosteroids (18.3% vs. 13.7%; aOR, 1.15 [CI, 1.00 to 1.32]) within 90 days of CDI diagnosis. Chronic kidney disease (10.4% vs. 5.6%; aOR, 1.49 [CI, 1.24 to 1.80]) and diagnosis in a nursing home (2.1% vs. 0.6%; aOR, 1.99 [CI, 1.34 to 2.93]) were also associated with increased risk for mrCDI. Limitation: The primary analyses included only commercially insured patients in the United States. Conclusion: Relative to CDI, mrCDI incidence has disproportionately increased, indicating a rising demand for mrCDI therapies. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases.

Early Versus Delayed Feeding in Patients With Acute Pancreatitis: A Systematic Review: Annals of Internal Medicine: Vol 166, No 12

Background: Acute pancreatitis is among the most common and costly reasons for hospitalization in the United States. Bowel rest, pain control, and intravenous fluids are the cornerstones of treatment, but early feeding might also be beneficial. Purpose: To compare length of hospital stay, mortality, and readmission in adults hospitalized with pancreatitis who received early versus delayed feeding. Data Sources: MEDLINE via Ovid, EMBASE, the Cochrane Library, CINAHL, and Web of Science through January 2017. Study Selection: Two authors independently reviewed and selected studies if they were randomized clinical trials, included adults hospitalized with acute pancreatitis, and compared early versus delayed feeding (≤48 vs. >48 hours after hospitalization). Data Extraction: Two investigators independently extracted study data and rated risk of bias using the Cochrane Collaboration tool. Data Synthesis: Eleven randomized trials (8 peer-reviewed publications, 3 abstract-only presentations) that included 948 patients were eligible. Seven trials (3 with low risk of bias) enrolled patients with mild to moderate pancreatitis. Four trials (1 with low risk of bias) included patients with predicted severe pancreatitis. Routes used for early feeding included oral (4 studies), nasogastric (2 studies), nasojejunal (4 studies), and oral or nasoenteric (1 study). Among patients with mild to moderate pancreatitis, early feeding was associated with reduced length of stay in 4 of 7 studies (including 2 of 3 with low risk of bias). Other outcomes were heterogeneous and variably reported, but no study showed an increase in adverse events with early feeding. Among patients with severe pancreatitis, limited evidence revealed no statistically significant difference in outcomes between early and delayed feeding. Limitation: Heterogeneity of feeding protocols and outcomes, scant data, and unclear or high risk of bias in several studies. Conclusion: Limited data suggest that early feeding in patients with acute pancreatitis does not seem to increase adverse events and, for patients with mild to moderate pancreatitis, may reduce length of hospital stay. Primary Funding Source: None. (PROSPERO: CRD42015016193)

Colorectal Cancer Screening in the United States: What Is the Best FIT?

Forbidden Topics

Historical Perspective on the Rise and Fall and Rise of Antibiotics and Human Weight Gain

In recent medical and popular literature, audiences have been asked to consider whether antibiotics have contributed to the rising obesity epidemic. Prominent magazines have stated that weight may be adversely affected by antibiotics that destroy existing microbiomes and replace them with less helpful ones. However, there is a long history of efforts to investigate the relationship between antibiotics and human weight gain. In the early 1950s, amid initial findings that low doses of antibiotics served as growth promoters in animal livestock, investigators explored the role of antibiotics as magic bullets for human malnutrition. Nevertheless, early enthusiasm was tempered by controlled studies showing that antibiotics did not serve as useful, nonspecific growth promoters for humans. In subsequent decades, against the backdrop of rising concern over antibiotic resistance, investigators studying the role of antibiotics in acute malnutrition have had to navigate a more complicated public health calculus. In a related historical stream, scientists since the 1910s have explored the role of the intestinal microflora in human health. By the 2000s, as increasing resources and more sophisticated tools were devoted to understanding the microbiome (a term coined in 2001), attention would turn to the role of antibiotics and the intestinal microflora in the rising obesity epidemic. Despite scientific and commercial enthusiasm, easy answers (whether about antibiotics or probiotics) have again given way to an appreciation for the complexity of human growth. History encourages caution about our hopes for simplistic answers for presumed “fat drugs” and slimming probiotics alike.