America, We Are Confused: The Updated U.S. Preventive Services Task Force Recommendation on Colorectal Cancer Screening

Are Microbial Politics Local?

Predicting the Prognosis of Acute Pancreatitis

Pioglitazone: An Addition to Our Toolbox for Patients With Diabetes and Nonalcoholic Steatohepatitis?

Treatment With Ledipasvir–Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial: Annals of Internal Medicine: Vol 166, No 2

Background: Use of interferon and ribavirin to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients is limited because of the risk for allograft rejection and poor tolerability. Objective: To evaluate the safety and efficacy of the interferon- and ribavirin-free regimen ledipasvir–sofosbuvir in kidney transplant recipients with chronic genotype 1 or 4 HCV infection. Design: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT02251717) Setting: 5 sites in Europe. Patients: Treatment-naive or -experienced kidney transplant recipients with chronic genotype 1 or 4 HCV infection, with or without compensated cirrhosis, and with an estimated glomerular filtration rate (eGFR) of 40 mL/min or greater were randomly assigned 1:1 to receive ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks. Measurements: The primary end point was sustained virologic response at 12 weeks after therapy ended (SVR12). Results: Among 114 patients, the median age was 53 years, 58% were male, 91% had genotype 1 infection, 69% were treatment naive, and 15% had compensated cirrhosis. The median eGFR was 56 mL/min (range, 35 to 135 mL/min). One hundred percent of patients (57 of 57) treated for 12 weeks (95% CI, 94% to 100%) and 100% of those (57 of 57) treated for 24 weeks (CI, 94% to 100%) achieved SVR12. Serious adverse events were reported in 13 patients (11%). Of these, 3 events—syncope, pulmonary embolism, and serum creatinine increase—in 3 patients were determined to be treatment related. One patient permanently discontinued treatment because of an adverse event (syncope). The most frequent adverse events overall were headache (n = 22 [19%]), asthenia (n = 16 [14%]), and fatigue (n = 11 [10%]). Limitations: The study was open label, no inferential statistics were planned, and only patients with genotype 1 or 4 infection were included. Few patients with HCV genotype 1a and cirrhosis were enrolled. Conclusion: Treatment with ledipasvir–sofosbuvir for 12 or 24 weeks was well-tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 1 or 4 infection, all of whom achieved SVR12. Primary Funding Source: Gilead Sciences.

Racial and Ethnic Disparities in Interval Colorectal Cancer Incidence: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 166, No 12

Background: Interval colorectal cancer (CRC) accounts for 3% to 8% of all cases of CRC in the United States. Data on interval CRC by race/ethnicity are scant. Objective: To examine whether risk for interval CRC among Medicare patients differs by race/ethnicity and whether this potential variation is accounted for by differences in the quality of colonoscopy, as measured by physicians' polyp detection rate (PDR). Design: Population-based cohort study. Setting: Medicare program. Participants: Patients aged 66 to 75 years who received colonoscopy between 2002 and 2011 and were followed through 2013. Measurements: Kaplan–Meier curves and adjusted Cox models were used to estimate cumulative probabilities and hazard ratios (HRs) of interval CRC, defined as a CRC diagnosis 6 to 59 months after colonoscopy. Results: There were 2735 cases of interval CRC identified over 235 146 person-years of follow-up. A higher proportion of black persons (52.8%) than white persons (46.2%) received colonoscopy from physicians with a lower PDR. This rate was significantly associated with interval CRC risk. The probability of interval CRC by the end of follow-up was 7.1% in black persons and 5.8% in white persons. Compared with white persons, black persons had significantly higher risk for interval CRC (HR, 1.31 [95% CI, 1.13 to 1.51]); the disparity was more pronounced for cancer of the rectum (HR, 1.70 [CI, 1.25 to 2.31]) and distal colon (HR, 1.45 [CI, 1.00 to 2.11]) than for cancer of the proximal colon (HR, 1.17 [CI, 0.96 to 1.42]). Adjustment for PDR did not alter HRs by race/ethnicity, but differences between black persons and white persons were greater among physicians with higher PDRs. Limitation: Colonoscopy and polypectomy were identified by using billing codes. Conclusion: Among elderly Medicare enrollees, the risk for interval CRC was higher in black persons than in white persons; the difference was more pronounced for cancer of the distal colon and rectum and for physicians with higher PDRs. Primary Funding Source: American Cancer Society.

Effectiveness of Screening Colonoscopy to Prevent Colorectal Cancer Among Medicare Beneficiaries Aged 70 to 79 Years: A Prospective Observational Study: Annals of Internal Medicine: Vol 166, No 1

Background: No randomized, controlled trials of screening colonoscopy have been completed, and ongoing trials exclude persons aged 75 years or older. The Medicare program, however, reimburses screening colonoscopy without an upper age limit. Objective: To evaluate the effectiveness and safety of screening colonoscopy to prevent colorectal cancer (CRC) in persons aged 70 to 74 and those aged 75 to 79 years. Design: Large-scale, population-based, prospective study. The observational data were used to emulate a target trial with 2 groups: colonoscopy screening and no screening. Setting: United States. Participants: 1 355 692 Medicare beneficiaries (2004 to 2012) aged 70 to 79 years at average risk for CRC who used Medicare preventive services and had no previous diagnostic or surveillance colonoscopies in the past 5 years. Measurements: 8-year risk for CRC and 30-day risk for adverse events. Results: In beneficiaries aged 70 to 74 years, the 8-year risk for CRC was 2.19% (95% CI, 2.00% to 2.37%) in the screening colonoscopy group and 2.62% (CI, 2.56% to 2.67%) in the no-screening group (absolute risk difference, −0.42% [CI, −0.24% to −0.63%]). Among those aged 75 to 79 years, the 8-year risk for CRC was 2.84% (CI, 2.54% to 3.13%) in the screening colonoscopy group and 2.97% (CI, 2.92% to 3.03%) in the no-screening group (risk difference, −0.14% [CI, −0.41 to 0.16]). The excess 30-day risk for any adverse event in the colonoscopy group was 5.6 events per 1000 individuals (CI, 4.4 to 6.8) in the 70- to 74-year age group and 10.3 per 1000 (CI, 8.6 to 11.1) in the 75- to 79-year age group. Limitation: CRC-specific mortality was not available, but CRC incidence and stage were studied at diagnosis. Conclusion: Screening colonoscopy may have had a modest benefit in preventing CRC in beneficiaries aged 70 to 74 years and a smaller benefit in older beneficiaries. The risk for adverse events was low but greater among older persons. Primary Funding Source: National Institutes of Health.

Prediction Models of Mortality in Acute Pancreatitis in Adults: A Systematic Review: Annals of Internal Medicine: Vol 165, No 7

Background: Acute pancreatitis (AP) varies in severity, prompting development of systems aimed at predicting prognosis to help guide therapy. Although several prediction approaches are available, their test characteristics and clinical utility are not completely understood. Purpose: To evaluate the test characteristics (prognostic accuracy, incremental predictive value) and clinical utility (effect on patient outcomes) of severity scores for predicting mortality in AP. Data Sources: Ovid MEDLINE and EMBASE (inception to 3 May 2016). Study Selection: Longitudinal studies, in any language, that evaluated the prognostic value of at least 1 clinical severity score in AP. Data Extraction: Dual data extraction and quality assessment. Data Synthesis: Of 4039 citations screened, 94 unique studies evaluating 18 scores in 53 547 patients met the inclusion criteria. All studies provided data on prognostic accuracy, whereas 6 provided data on incremental predictive values. Most scores demonstrated low prognostic accuracy. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson criteria were studied most extensively. The median sensitivity and specificity of APACHE II at a threshold of 7 were 100% (range, 68% to 100%) and 63% (range, 21% to 96%), respectively, and those of the Ranson criteria at a threshold of 2 were 90% (range, 0% to 100%) and 67% (range, 14% to 97%), respectively. Estimates of sensitivity were based on relatively few patients. Evidence was limited regarding the incremental predictive value of the scoring systems or their effect on patient outcomes. Limitation: Substantial clinical heterogeneity and inadequate methodological and reporting quality precluded a meta-analysis. Conclusion: The test characteristics and clinical utility of AP severity scores remain uncertain. Additional studies with improved methodological rigor are needed, and the development of new scoring systems may be justified. Primary Funding Source: Global Scholarship Programme for Research Excellence for 2014 to 2015, The Chinese University of Hong Kong.

Realizing HOPE: The Ethics of Organ Transplantation From HIV-Positive Donors

The HIV Organ Policy Equity (HOPE) Act now allows transplantation of organs from HIV-positive living and deceased donors to HIV-positive individuals with end-stage organ disease in the United States. Although clinical experience with such transplants is limited to a small number of deceased-donor kidney transplants from HIV-positive to HIV-positive persons in South Africa, unprecedented HIV-positive–to–HIV-positive liver transplantations and living-donor kidney transplantations are also now on the horizon. Initially, all HIV-positive–to–HIV-positive transplantations will occur under research protocols with safeguards and criteria mandated by the National Institutes of Health. Nevertheless, this historic change brings ethical opportunities and challenges. For HIV-positive individuals needing an organ transplant, issues of access, risk, and consent must be considered. For potential HIV-positive donors, there are additional ethical challenges of privacy, fairness, and the right to donate. Careful consideration of the ethical issues involved is critical to the safe and appropriate evaluation of this novel approach to transplantation.

Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review: Annals of Internal Medicine: Vol 165, No 8

Background: Biosimilars are of growing clinical, regulatory, and commercial importance. Purpose: To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors. Data Sources: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016. Study Selection: Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-α inhibitor with a reference biologic in humans. Data Extraction: Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality. Data Synthesis: Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes. Limitation: Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars. Conclusion: Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors. Primary Funding Source: Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262)