Benjamin P. Linas

Priorities for screening and treatment of latent tuberculosis infection in the United States.

RATIONALE To improve the effectiveness of tuberculosis (TB) control programs in the United States by identifying cost-effective priorities for screening for latent tuberculosis infection (LTBI). OBJECTIVES To estimate the cost-effectiveness of LTBI screening using the tuberculin skin test (TST)and interferon-g release assays (IGRAs). METHODS A Markov model of screening for LTBI with TST and IGRA in risk-groups considered in current LTBI screening guidelines. MEASUREMENTS AND MAIN RESULTS In all risk-groups, TST and IGRA screening resulted in increased mean life expectancy, ranging from 0.03–0.24 life-months per person screened. IGRA screening resulted in greater life expectancy gains than TST. Screening always cost more than not screening, but IGRA was cost-saving compared with TST in some groups. Four patterns of cost-effectiveness emerged, related to four risk categories. (1) Individuals at highest risk of TB reactivation (close contacts and those infected with HIV): the incremental cost-effectiveness ratio (ICER) of IGRA compared with TST was less than

The Hepatitis C Cascade of Care: Identifying Priorities to Improve Clinical Outcomes

100,000 per quality-adjusted life year (QALY) gained. (2) The foreign-born: IGRA was cost-saving compared with TST and cost-effective compared with no screening (ICER ,

Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis

100,000 per QALY gained). (3) Vulnerable populations (e.g., homeless, drug user, or former prisoner): the ICER of TST screening was approximately

Cost-effective Screening for Acute Hepatitis C Virus Infection in HIV-Infected Men Who Have Sex With Men

100,000–

Assessing the Impact of Federal HIV Prevention Spending on HIV Testing and Awareness

150,000 per QALY gained, but IGRA was not cost-effective. (4) Medical comorbidities (e.g., diabetes): the ICER of screening with TST or IGRA was greater than

Cost-effectiveness of rapid hepatitis C virus (HCV) testing and simultaneous rapid HCV and HIV testing in substance abuse treatment programs.

100,000 per QALY. CONCLUSIONS LTBI screening guidelines could make progress toward TB elimination by prioritizing screening for close contacts, those infected with HIV, and the foreign-born regardless of time living in the United States. For these groups, IGRA screening was more cost-effective than TST screening.

New York State pharmacists' attitudes toward needle and syringe sales to injection drug users before implementation of syringe deregulation.

Background As highly effective hepatitis C virus (HCV) therapies emerge, data are needed to inform the development of interventions to improve HCV treatment rates. We used simulation modeling to estimate the impact of loss to follow-up on HCV treatment outcomes and to identify intervention strategies likely to provide good value for the resources invested in them. Methods We used a Monte Carlo state-transition model to simulate a hypothetical cohort of chronically HCV-infected individuals recently screened positive for serum HCV antibody. We simulated four hypothetical intervention strategies (linkage to care; treatment initiation; integrated case management; peer navigator) to improve HCV treatment rates, varying efficacies and costs, and identified strategies that would most likely result in the best value for the resources required for implementation. Main measures Sustained virologic responses (SVRs), life expectancy, quality-adjusted life expectancy (QALE), costs from health system and program implementation perspectives, and incremental cost-effectiveness ratios (ICERs). Results We estimate that imperfect follow-up reduces the real-world effectiveness of HCV therapies by approximately 75%. In the base case, a modestly effective hypothetical peer navigator program maximized the number of SVRs and QALE, with an ICER compared to the next best intervention of

Cost-effectiveness of surveillance strategies after treatment for high-grade anal dysplasia in high-risk patients.

48,700/quality-adjusted life year. Hypothetical interventions that simultaneously addressed multiple points along the cascade provided better outcomes and more value for money than less costly interventions targeting single steps. The 5-year program cost of the hypothetical peer navigator intervention was

The cost-effectiveness of improved hepatitis C virus therapies in HIV/hepatitis C virus coinfected patients.

14.5 million per 10,000 newly diagnosed individuals. Conclusions We estimate that imperfect follow-up during the HCV cascade of care greatly reduces the real-world effectiveness of HCV therapy. Our mathematical model shows that modestly effective interventions to improve follow-up would likely be cost-effective. Priority should be given to developing and evaluating interventions addressing multiple points along the cascade rather than options focusing solely on single points.

Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population

Background Diagnosis of chronic Hepatitis C Virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid test (NAT). HCV core antigen (HCVcAg) is a potential alternative to NAT.Approximately 130 to 150 million persons are infected with chronic hepatitis C virus (HCV), and approximately 75% of all cases occur in low- and middle-income countries (LMICs) (1, 2). Direct-acting antivirals allow safe and effective curative treatment, but treatment is the final step in a long cascade that requires screening, confirmation, notification of results, and linkage to care (3, 4). Diagnosis of HCV is a 2-step process that starts with screening for exposure with an assay that detects antibodies to HCV (anti-HCV), followed by nucleic acid testing (NAT) for persons with reactive anti-HCV to confirm active viremia. Among those who acquire a primary infection, 15% to 50% will spontaneously clear the virus within the first 2 to 6 months and remain positive for anti-HCV, although they are not actively infected and do not require treatment (5). The diagnostic process is designed to be cost-effective, with a low-cost screening test followed by targeted testing with the more expensive NAT. In LMICs, implementation of a complex algorithm is often not feasible and diagnostic capacity is low; as a result, fewer than 1% of patients are aware of their infection (6). In addition, a significant proportion of patients who test positive for anti-HCV do not receive diagnostic NAT and are lost to follow-up (7). The 2-step diagnostic process is a major bottleneck to the HCV cascade of care that needs to be addressed to achieve the ambitious elimination strategy proposed by the World Health Organization (WHO) (8). Testing for hepatitis C virus core antigen (HCVcAg) is a potential replacement for NAT. The HCVcAg forms the internal capsid, which is highly conserved and antigenic (9, 10). During viral assembly, nucleocapsid peptide 22 is released into the plasma (11) and can be detected earlier than antibodies and throughout the course of infection (12). The following 5 tests for HCVcAg detection are commercially available: Abbott ARCHITECT HCV Ag, which is an automated chemiluminescent microparticle immunoassay; Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag, which are similar automated chemiluminescent enzyme immunoassays available in Japan and China; Hunan Jynda Bioengineering Group HCV Ag enzyme-linked immunosorbent assay (ELISA); and Ortho HCV Ag ELISA. Although all current HCVcAg tests require laboratory capacity, the development of a highly sensitive point-of-care (POC) platform is feasible and probably possible at a lower cost than NAT POC. Such a test has been defined as the highest-priority target product profile in a global stakeholder consultation process (13). As such, tests targeting HCVcAg could be attractive as a single-step diagnosis for chronic HCV infection in high-prevalence settings, which would streamline the HCV cascade of care and reduce loss to follow-up. This WHO-commissioned systematic review to inform forthcoming WHO guidelines on hepatitis testing evaluated the accuracy of diagnosis of active HCV infection among adults and children for 5 commercially available HCVcAg tests compared with NAT. Methods We performed a systematic review of HCV diagnostics literature, extracted data from selected studies, and conducted a bivariate meta-analysis of the test characteristics of HCVcAg as a diagnostic test for HCV infection. We used standard methods for systematic reviews and meta-analyses of diagnostic tests (1418), including preparation of an a priori protocol for the literature search, article selection, data extraction, quality assessment, and analysis (see Supplement). Supplement. Data Supplement Data Sources and Searches We searched EMBASE, PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews for citations related to HCVcAg screening and diagnosis published until 31 March 2016. We did not restrict the search by language, and terms were selected under the guidance of medical librarians. The search strategies included terms related to HCV, antigen, and nucleic acid amplification. See the Supplement for specific search strategies and the number of studies retrieved from each database. Two authors (J.M.F. and T.M.T.) independently assessed titles and abstracts identified by the literature search to select eligible studies. Citations identified by either reviewer were selected for full-text review. These same 2 authors then independently assessed the full-text articles using predefined inclusion and exclusion criteria. Discrepancies were resolved by discussion between the authors and, when needed, by the decision of a third author (C.M.D.). Study Selection Inclusion criteria were as follows: casecontrol, cross-sectional, cohort, or randomized trials; commercially available HCVcAg tests; commercially available NAT as the reference standard; whole blood, plasma, or serum specimens; and at least 10 independent clinically collected samples. Studies done using commercially prepared reference panel specimens, published in abstract form only, or presented as slides or posters were excluded. We included articles that reported results from populations with any distribution of patient age, from any country, and in any screening setting (for example, hospital- or community-based). Although we were primarily interested in test performance among persons at risk for HCV and with known infection, we also included studies using specimens from healthy blood donors. Because the performance characteristics of NAT are very similar when HCV RNA levels are greater than 50 IU/mL, we accepted any of the following NAT techniques as the reference standard: polymerase chain reaction, branched-chain DNA, or transcription-mediated amplification. Tests were classified as either qualitative or quantitative. Data Extraction and Quality Assessment Two authors (J.M.F. and T.M.T.) independently assessed all studies for inclusion and extracted data on study methods, characteristics, and test accuracy using a standardized extraction form (Supplement). Foreign-language studies were translated and extracted by native speakers using the same form. We crosschecked data points for 25% of the included studies. Disagreements between reviewers were resolved by discussion or by a third reviewer (C.M.D.). When elements for extraction were missing, we contacted the authors to request further data. We also requested individual specimen data to allow for a quantitative assessment of HCVcAg against HCV RNA. Studies without extractable sensitivity and specificity data were excluded if no further information was acquired after 3 attempts to contact the study authors. Methodological quality of the included studies was assessed using a validated QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool (19). Details of the QUADAS-2 questions and interpretation are reported in the Supplement. Data Synthesis and Analysis We defined HCVcAg sensitivity as the proportion of samples with a positive NAT result that was also positive for HCVcAg. We defined HCVcAg specificity as the proportion of samples with a negative NAT result that was also negative for HCVcAg. Sensitivity and specificity were the primary outcome measures. Positive and negative likelihood ratios were calculated when pooled sensitivity and specificity data were available from meta-analysis. Indeterminate test results accounted for fewer than 1% for all index tests and were excluded from further analyses. We constructed forest plots for each HCVcAg index test to visually assess heterogeneity by examining the CIs of individual studies. We then used summary plots to examine the width of the prediction region, with a wider prediction region suggesting more heterogeneity. When at least 4 studies with limited heterogeneity were available, we used a bivariate random-effects model and carried out meta-analyses using the metandi command in STATA, version 14 (StataCorp) (20, 21). When at least 4 studies provided sensitivity data only, we did a univariate random-effects meta-analysis on the sensitivities to use all available data. Results from the univariate analyses (including all studies) were compared with the pooled estimates from the bivariate analyses where possible. Descriptive analyses were done for index tests with fewer than 4 studies and when substantial heterogeneity was evident from inspection of the forest and summary plots. When quantitative data were available, a locally weighted regression smoother was used to visually assess the linearity of quantitative HCVcAg (measured in fmol/L) to HCV RNA (measured in IU/mL) (22). We identified outliers and recorded descriptive statistics of these points. Quantitative data were insufficient to assess any test other than Abbott ARCHITECT. We assessed for publication bias when more than 10 studies were available for an index test. We generated funnel plots displaying the log diagnostic odds ratio versus the SE for each study (18). We also did the trim-and-fill statistical assessment in STATA using the metatrim command (23). Unpublished data were not included. All statistical analyses were done using STATA and R, version 3.2.5 (R Foundation for Statistical Computing). Role of the Funding Source This systematic review was supported by the National Institutes of Health, which had no direct involvement in the study design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Study Selection and Characteristics The systematic review identified 8508 citations, from which we reviewed 299 full-text articles and identified 44 that met the a prioridefined inclusion criteria (Appendix Figure 1). Of the included studies, 44 used the 5 HCVcAg assays; 1 of these studies directly compared 3 antigen tests. Four studies were translated from Mandarin (2427), 1 from German (28), and 2 from Japanese (29, 30). Characteristics for each study are presented in Table 1. Table 1. Characteristics of Included Studies Grouped Alphabetically, by Index Test Type Appendix Fig