The cost-effectiveness of universal hepatitis B screening for reaching WHO diagnosis targets in Australia by 2030.

OBJECTIVES: To assess the impact on diagnosis targets, cost, and cost-effectiveness of universal hepatitis B screening in Australia. DESIGN: Markov model simulation of disease and care cascade progression for people with chronic hepatitis B in Australia. SETTING: Three scenarios were compared: 1. no change to current hepatitis B virus (HBV) testing practice; 2. universal screening strategy, with the aim of achieving the WHO diagnosis target by 2030 (90% of people with chronic hepatitis B diagnosed), based on opportunistic (general practitioner-initiated) screening for HBsAg; 3. universal screening strategy, and also ensuring that 50% of people with chronic hepatitis B are receiving appropriate clinical management by 2030. MAIN OUTCOME MEASURES: Projected care cascade for people with chronic hepatitis B, cumulative number of HBV-related deaths, intervention costs, and health utility (quality-adjusted life-years [QALYs] gained during 2020-2030). An incremental cost-effectiveness ratio (ICER) threshold (v scenario 1) of $50 000 per QALY gained was applied. RESULTS: Compared with scenario 1, 80 HBV-related deaths (interquartile range [IQR], 41-127 deaths) were averted during 2020-2030 in scenario 2, 315 HBV-related deaths (IQR, 211-454 deaths) in scenario 3. Scenario 2 cost $84 million (IQR, $41-106 million) more than scenario 1 during 2020-2030 (+8%), yielding an ICER of $104 921 (IQR, $49 587-107 952) per QALY gained. Scenario 3 cost $263 million (IQR, $214-316 million) more than scenario 1 during 2020-2030 (+24%), yielding an ICER of $47 341 (IQR, $32 643-58 200) per QALY gained. Scenario 3 remained cost-effective if the test positivity rate was higher than 0.35% or the additional costs per person tested did not exceed $4.02. CONCLUSIONS: Universal screening for hepatitis B will be cost-effective only if the cost of testing is kept low and people receive appropriate clinical management.

Controlled temperature chain for vaccination in low- and middle-income countries: a realist evidence synthesis.

Objective: To evaluate the evidence describing how the controlled temperature chain approach for vaccination could lead to improved equitable immunization coverage in low- and middle-income countries. Methods: We created a theory of change construct from the Controlled temperature chain: strategic roadmap for priority vaccines 2017-2020, containing four domains: (i) uptake and demand for the approach; (ii) compliance and safe use of the approach; (iii) programmatic efficiency gains from the approach; and (iv) improved equitable immunization coverage. To verify and improve the theory of change, we applied a realist review method to analyse published descriptions of controlled temperature chain or closely related experiences. Findings: We evaluated 34 articles, describing 22 unique controlled temperature chain or closely related experiences across four World Health Organization regions. We identified a strong demand for this approach among service delivery providers; however, generating an equal level of demand among policy-makers requires greater evidence on economic benefits and on vaccination coverage gains, and use case definitions. Consistent evidence supported safety of the approach when integrated into special vaccination programmes. Feasible training and supervision supported providers in complying with protocols. Time-savings were the main evidence for efficiency gains, while cost-saving data were minimal. Improved equitable coverage was reported where vaccine storage beyond the cold chain enabled access to hard-to-reach populations. No evidence indicated an inferior vaccine effectiveness nor increased adverse event rates for vaccines delivered under the approach. Conclusion: Synthesized evidence broadly supported the initial theory of change. Addressing evidence gaps on economic benefits and coverage gains may increase future uptake.

Factors predictive of sexual violence: Testing the four pillars of the Confluence Model in a large diverse sample of college men.

This article focuses on the characteristics of sexually violent men who have not been convicted of a crime. The objective of this study was to test the four key interrelated pillars of the Confluence Model. The first key pillar posits the interaction of Hostile Masculinity and Impersonal Sex as core risk predictors. The second pillar entails a "mediated structure" wherein the impact of more general risk factors is mediated via those specific to aggression against women. The third pillar comprises a single latent factor underlying various types of sexual violence. The fourth pillar expands the core model by including the secondary risk factors of lower empathy, peer support, extreme pornography use, and participation in alcohol parties. An ethnically diverse sample of 1,148 male students from 13 U.S. colleges and universities completed a comprehensive survey that assessed the hypothesized risk factors and self-reported sexual violence, which included noncontact sexual offenses, contact sexual coercion, and contact sexual aggression. A series of multiple regression analyses were conducted before testing structural equation models. The results supported the integration of the four pillars within a single expanded empirical model that accounted for 49% of the variance of sexual violence. This study yielded data supporting all four key pillars. These findings provide information about non-redudant risk factors that can be used to develop screening tools, group-based and individually tailored psychoeducational and treatment interventions.

Enhancing the hepatitis B care cascade in Australia: A cost-effectiveness model.

If Australia is to successfully eliminate hepatitis B as a public health threat, it will need to enhance the chronic hepatitis B (CHB) care cascade. This study used a Markov model to assess the impact, cost and cost-effectiveness of scaling up CHB diagnosis, linkage to care and treatment to reach national and international elimination targets for hepatitis B in Australia. Compared to continued current trends, the model calculated the difference in care cascade projection, disability-adjusted life years (DALYs), costs and the incremental cost-effectiveness ratio (ICER), of scaling up CHB diagnosis, linkage to care and treatment to reach: (a) Australia's 2022 national targets and (b) the WHO's 2030 global targets. Achieving the national and WHO targets had ICERs of A$13 435 (A$10 236-A$21 165) and A$14 482 (A$13 031-A$25 641) per DALY averted between 2016 and 2030 in Australia, respectively. However, this excluded implementation and demand generation costs. The ICER for the National Strategy and WHO Strategy remained under A$50 000 per DALY averted if Australia spent up to A$328 or A$538 million, respectively, per annum (for 2016-2030) on implementation and demand generation activities. Sensitivity analysis showed that cost-effectiveness was predominately driven by the cost of CHB treatment and influenced by disease progression rates. Hence for Australia to reach the National Hepatitis B Strategy 2022 targets and WHO Strategy 2030 targets, it requires an improvement in the CHB care cascade. We estimated it is cost-effective to spend up to A$328 million or A$538 million per year to reach the National and WHO Strategy targets, respectively.

A harmonization effort for acceptable daily exposure derivation - Considerations for application of adjustment factors.

Acceptable daily exposures (ADEs) are established to determine the quantity of one drug substance that can contaminate another drug product without causing harm to the patient. An important part in setting an ADE for a drug substance, after identification of the unwanted critical effect(s) of the compound (see Bercu et al., 2016, this issue), is the determination of an appropriate overall margin of safety that is need to be maintained below the dose causing a certain critical effect (i.e., the point of departure or PoD). The overall margin of safety used to protect the general patient population from critical effects is derived as the product (i.e., composite adjustment factor) of various individual factors that account for variability and uncertainty in extrapolating from the PoD to an ADE. These factors address the considerations of interindividual variability, interspecies extrapolation, LOAEL-to-NOAEL extrapolation, exposure duration adjustment, effect severity, and database completeness. The factors are considered individually, but are not necessarily independent and their interdependence should be identified, with subsequent adjustment to the composite factor, as appropriate. It is important to identify all sources of variability and uncertainty pertinent to the derivation of the ADE and ensure each is considered in the assessment, at least by one of the adjustment factors. This manuscript highlights the basis for and selection of factors that address variability and uncertainty as used in the guidance documents on setting ADEs or other related health-based limits.

Using default methodologies to derive an acceptable daily exposure (ADE).

This manuscript discusses the different historical and more recent default approaches that have been used to derive an acceptable daily exposure (ADE). While it is preferable to derive a health-based ADE based on a complete nonclinical and clinical data package, this is not always possible. For instance, for drug candidates in early development there may be no or limited nonclinical or clinical trial data. Alternative approaches that can support decision making with less complete data packages represent a variety of methods that rely on default assumptions or data inputs where chemical-specific data on health effects are lacking. A variety of default approaches are used including those based on certain toxicity estimates, a fraction of the therapeutic dose, cleaning-based limits, the threshold of toxicological concern (TTC), and application of hazard banding tools such as occupational exposure banding (OEB). Each of these default approaches is discussed in this manuscript, including their derivation, application, strengths, and limitations. In order to ensure patient safety when faced with toxicological and clinical data-gaps, default ADE methods should be purposefully as or more protective than ADEs derived from full data packages. Reliance on the subset of default approaches (e.g., TTC or OEB) that are based on toxicological data is preferred over other methods for establishing ADEs in early development while toxicology and clinical data are still being collected.

A global investment case for hepatitis B elimination: a modelling study.

Hepatitis B is estimated to cause 500 000-900 000 deaths globally each year. WHO has targets for elimination by 2030; however, progress has stalled due to multiple barriers, notably a paucity of global funding and insufficient evidence on the economic burden of disease. Using a dynamic mathematical model of hepatitis B transmission, disease progression, and mortality in the six WHO regions, we estimate the costs and benefits of reaching 90% vaccination, 90% diagnosis, and 80% treatment coverage by either 2030 (as targeted), 2040, or 2050. Without increased intervention coverage, hepatitis B mortality was estimated to cost US$784·35 billion (95% Crl 731·63-798·33 billion) globally in lost productivity over 2022-50. Achieving targets by 2030 averted 25·64 million infections (95% Crl 17·39-34·55 million) and 8·63 million hepatitis B-attributable deaths (95% Crl 7·12-9·74 million) over 2022-50. This achievement incurred an incremental cost of $2934·55 (95% Crl 2778·55-3173·52) per disability-adjusted life year averted by 2050 under a health systems perspective, and was cost-saving with a net economic benefit of $99·03 billion (95% Crl 78·66-108·96 billion) by 2050 from a societal perspective. Delayed achievement of intervention coverage targets had reduced health and economic benefits. These findings highlight that hepatitis B is an underappreciated cause of economic burden and show investment toward elimination will probably yield substantial returns.

Human chromosome 11 DNA sequence and analysis including novel gene identification.

Chromosome 11, although average in size, is one of the most gene- and disease-rich chromosomes in the human genome. Initial gene annotation indicates an average gene density of 11.6 genes per megabase, including 1,524 protein-coding genes, some of which were identified using novel methods, and 765 pseudogenes. One-quarter of the protein-coding genes shows overlap with other genes. Of the 856 olfactory receptor genes in the human genome, more than 40% are located in 28 single- and multi-gene clusters along this chromosome. Out of the 171 disorders currently attributed to the chromosome, 86 remain for which the underlying molecular basis is not yet known, including several mendelian traits, cancer and susceptibility loci. The high-quality data presented here--nearly 134.5 million base pairs representing 99.8% coverage of the euchromatic sequence--provide scientists with a solid foundation for understanding the genetic basis of these disorders and other biological phenomena.

Evaluating the potential cost-effectiveness of microarray patches to expand access to hepatitis B birth dose vaccination in low-and middle-income countries: A modelling study.

Timely birth dose vaccination is key for achieving elimination of hepatitis B, however, programmatic requirements for delivering current vaccine presentations to births outside of health facilities inhibits coverage within many low-and middle-income countries (LMICs). Vaccine technologies in development such as microarray patches (MAPs) could assist in overcoming these barriers, but procurement could incur higher per-dose commodity costs than current ten-dose (US$0.34) and single-dose (US$0.62) vial presentations, necessitating an evaluation of the economic value proposition for MAPs. Within 80 LMICs offering universal hepatitis B birth dose vaccination, the cost-effectiveness of using MAPs to expand coverage was evaluated using a mathematical model. We considered three potential per dose MAP prices (US$1.65, US$3.30, and US$5.00), and two potential MAP use-cases: (1) MAPs are used by lay-health workers to expand birth dose coverage outside of health facility settings, and (2) MAPs are also preferred by qualified health workers, replacing a proportion of existing coverage from vaccine vials. Analysis took the health system perspective, was costed in 2020 US$, and discounted at 3% annually. Across minimal (1% additional coverage) and maximal (10% additional and 10% replacement coverage) MAP usage scenarios, between 2.5 (interquartile range [IQR]: 1.9, 3.1) and 38 (IQR: 28,44) thousand DALYs were averted over the estimated 2020 birth cohort lifetime in 80 LMICs. Efficiency of MAPs was greatest when used to provide additional coverage (scenario 1), on average saving US$88.65 ($15.44, $171.22) per DALY averted at a price of US$5.00 per MAP. Efficiency was reduced when used to replace existing coverage (scenario 2); however, at prices up to US$5.00 per MAP, we estimate this use-case could remain cost-effective in at least 73 (91%) modelled LMICs. Our findings suggest even at higher procurement costs, MAPs are likely to represent a highly cost-effective or cost-saving mechanism to expand reach of birth dose vaccination in LMICs.

Use of controlled temperature chain and compact prefilled auto-disable devices to reach 2030 hepatitis B birth dose vaccination targets in LMICs: a modelling and cost-optimisation study.

BACKGROUND: Hepatitis B causes more than 800 000 deaths globally each year. Perinatal infections are a major driver of this burden but can be prevented by vaccination within 24 h of birth. Currently, only 44% of newborn babies in low-income and middle-income countries (LMICs) receive a timely birth dose. We investigated the effects and cost-effectiveness of implementing ambient storage of hepatitis B vaccines under a controlled temperature chain (CTC) protocol and the use of compact prefilled auto-disable (CPAD) devices for community births. METHODS: In this mathematical modelling study of perinatal hepatitis B transmission and disease progression, we estimated the coverage impact and cost-effectiveness of implementing CTC and CPAD interventions in the six Global Burden of Disease (GBD) regions containing LMICs. Combinations of four different scenarios of birth dose delivery strategies (cold chain, CTC) and interventions (needle and syringe, CPAD) were modelled across facility or community birth locations. We also estimated the minimum cost and most cost-effective strategy to achieve the WHO 90% hepatitis B birth dose coverage target in GBD regions and in 46 LMICs with a reported coverage of less than 90%. FINDINGS: Current delivery protocols achieved a maximum coverage of 65% (IQR 64-65) across GBD regions. Reaching 90% hepatitis B birth dose coverage across all GBD regions was estimated to cost a minimum of US$687·5 million per annum ($494·0 million more than the estimated current expenditure), of which $516·5 million (75%) was required for CTC and CPAD interventions. Reaching 90% coverage in this way was estimated to be cost saving in five of the six regions (and in 40 of 46 LMICs individually assessed) due to the disease costs averted, with the cost per disability-adjusted life-years averted being less than $83·27 otherwise. INTERPRETATION: Hepatitis B birth dose coverage of 90% is unlikely to be reached under current protocols. CTC and CPAD vaccine strategies present cost-effective solutions to overcome coverage barriers. FUNDING: The Burnet Institute.

Self-collected compared with professional-collected swabbing in the diagnosis of influenza in symptomatic individuals: A meta-analysis and assessment of validity.

Self-collected nasal swabs offer a cheaper alternative to professional-collected swabs for influenza testing. However, the diagnostic accuracy of self-collection has not been quantitatively reviewed. We identified 14 studies that compared diagnostic accuracy of self-collected to professional-collected swabs in influenza symptomatic individuals. Self-collected swabs were found to be highly acceptable, simple and comfortable to use. Data from nine studies were meta-analyzed. Pooled sensitivity was 87% (95% CI: 80%, 92%) and specificity was 99% (95% CI: 98%, 100%), compared to professional-collected swabs in the diagnosis of influenza. Pooled sensitivity and specificity estimates were used to assess the potential bias that would be introduced in studies had self-collected rather than professional-collected samples been used. While self-collected swabbing should not replace the role of clinical testing, our findings support the use of self-collected swabs for influenza research and surveillance. This method will be an important tool for evaluating novel influenza vaccines and vaccination strategies.

Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature.

BACKGROUND: Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the management of CIA do not yet include all currently approved ESPs or all of the clinically relevant benefits and risks of ESPs. OBJECTIVES: The aims of this work were to provide up-to-date assessments of the clinical efficacy and effectiveness (ie, transfusions and quality-of-life [QoL] benefits) and safety (ie, risk of venous thromboembolism [VTE] and all-cause or treatment-associated death) of epoetin-alfa, epoetin-beta, and darbepoetin-alfa for the treatment of CIA in cancer patients with hemoglobin<11 g/dL. We also considered the impact of differences in study design, patients, and treatments on the results. METHODS: A systematic review of the literature was performed to identify and analyze English-language studies (controlled trials and prospective uncontrolled studies with >or=300 patients) published between 1980 and July 2005. The databases searched were MEDLINE and the Cochrane Library. Relevant abstracts from the last 2 annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology were also included. Studies were selected, using predefined eligibility criteria. Two reviewers had to agree on all included and excluded studies, and on all data extracted from each accepted study before they were entered into a relational database. Meta-analyses were performed to quantify benefit and risk outcomes. RESULTS: In total, 40 studies including 21,378 patients were eligible for analysis. Each ESP was found to have efficacy relative to standard care or placebo. The odds ratio (OR) for transfusions in studies of epoetin versus controls was 0.44 (95% CI, 0.35-0.55) and of darbepoetin versus controls was 0.41 (95% CI, 0.31-0.55). Patients receiving ESPs experienced a significant improvement in QoL; the mean difference in Functional Assessment of Cancer Therapy-Fatigue score for ESPs versus controls was 0.23 (95% CI, 0.10-0.36; P=0.001). The frequency of VTE and death was not significantly different between ESPs and control (VTE OR, 1.41 [95% CI, 0.81-2.47]; all-cause mortality OR, 1.00 [95% CI, 0.69-1.44]). CONCLUSIONS: This analysis of key clinical benefits and risks of epoetin and darbepoetin in the treatment of CIA found no clinically relevant differences between these drugs.

An evaluation of a cultured human corneal epithelial tissue model for the determination of the ocular irritation potential of pharmaceutical process materials.

Irritation and other forms of local toxicity following contact with eyes is a potentially serious problem arising from occupational exposure to chemicals. Traditionally, evaluation of the irritant potential of novel chemicals has relied on the use of in vivo studies with rabbits. Concerns about the predictive potential of in vivo methods for human hazard and demand for economical and rapid screening of chemicals has stimulated a great deal of work to investigate in vitro alternatives for evaluating ocular irritation potential. This publication describes a screening study to assess a reconstituted corneal epithelial culture system, as an alternative for testing for ocular irritation with pharmaceutical process materials, extending the chemical domain with which this system has been tested. A total of 21 test chemicals were applied to commercially supplied reconstituted human corneal epithelial (HCE) cultures and effects on tissue viability (MTT reduction assay), tissue histology and IL-alpha expression were assessed. Positive controls (0.5% and 1% SDS) showed dose- and time-related adverse effects on tissues, consistent with known irritant effects. Negative controls showed no histological changes and retained high viability throughout the time-course of the experiment. Concordance was excellent with accuracy at each sampling time point of over 80% when viability (MTT reduction) was compared with existing EU classification of the test articles for ocular irritation (classification based on results of in vivo evaluation). Tissue viability as estimated by MTT reduction appears most useful as the primary means of assessing the irritation potential of the chemicals. Histopathological examination generally agreed with the results of the MTT assay. However, the use of cytokine analysis will need further consideration as results for this parameter showed no relationship with known irritation potential. These results infer that HCE cultures, alone or as a part of a tiered hazard screening programme, have promise for use in reducing reliance on live subject tests and contribute to generation of an appropriate hazard classification and label advice.

A proposed eye irritation testing strategy to reduce and replace in vivo studies using Bottom-Up and Top-Down approaches.

In spite of over 20 years of effort, no single in vitro assay has been developed and validated as a full regulatory replacement for the Draize Eye Irritation test. However, companies have been using in vitro methods to screen new formulations and in some cases as their primary assessment of eye irritation potential for many years. The present report shows the outcome of an Expert Meeting convened by the European Centre for the Validation of Alternative Methods in February 2005 to identify test strategies for eye irritation. In this workshop test developers/users were requested to nominate methods to be considered as a basis for the identification of such testing strategies. Assays were evaluated and categorized based on their proposed applicability domains (e.g., categories of irritation severity, modes of action, chemical class, physicochemical compatibility). The analyses were based on the data developed from current practice and published studies, the ability to predict depth of injury (within the applicable range of severity), modes of action that could be addressed and compatibility with different physiochemical forms. The difficulty in predicting the middle category of irritancy (e.g. R36, GHS Categories 2A and 2B) was recognized. The testing scheme proposes using a Bottom-Up (begin with using test methods that can accurately identify non-irritants) or Top-Down (begin with using test methods that can accurately identify severe irritants) progression of in vitro tests (based on expected irritancy). Irrespective of the starting point, the approach would identify non-irritants and severe irritants, leaving all others to the (mild/moderate) irritant GHS 2/R36 categories.

Does one size fit all? What we can and can't learn from a meta-analysis of housing models for persons with mental illness.

OBJECTIVE: Numerous studies have evaluated the impacts of community housing models on outcomes of persons with severe mental illness. The authors conducted a meta-analysis of 44 unique housing alternatives described in 30 studies, which they categorized as residential care and treatment, residential continuum, permanent supported housing, and nonmodel housing. Outcomes examined included housing stability, symptoms, hospitalization, and satisfaction. METHODS: Outcome scores were converted to effect size measures appropriate to the data. Effect sizes were combined to estimate random effects for housing models, which were then compared. RESULTS: All models achieved significantly greater housing stability than nonmodel housing. This effect was greatest for permanent supported housing (effect size=.63, p<.05). No differences between housing models were significant. For reduction of psychiatric symptoms, only residential care and treatment differed from nonmodel housing (effect size=.65, p<.05). For hospitalization reduction, both residential care and treatment and permanent supported housing differed from nonmodel housing (p<.05). Permanent supported housing achieved the highest effect size (.73) for satisfaction and differed from nonmodel housing and residential care and treatment (p<.001 and p<.05, respectively). CONCLUSIONS: The meta-analysis provides quantitative evidence that compared with nonmodel housing, housing models contribute to stable housing and other favorable outcomes. The findings also support the theory that different housing models achieve different outcomes for different subgroups. Data were not sufficient to fully answer questions designed to enable program planners and providers to better meet consumers' needs. It is important to answer these questions with research that uses common measures and adheres to scientific conventions.

Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy.

Effective treatment of tuberculosis requires adherence to a minimum of 6 months treatment with multiple drugs. To improve adherence and cure rates, directly observed therapy is recommended for the treatment of pulmonary tuberculosis. We compared treatment outcomes among all culture-positive patients treated for active pulmonary tuberculosis (n = 372) in San Francisco County, California from 1998 through 2000. Patients treated by directly observed therapy at the start of therapy (n = 149) had a significantly higher cure rate compared with patients treated by self-administered therapy (n = 223) (the sum of bacteriologic cure and completion of treatment, 97.8% versus 88.6%, p < 0.002), and decreased tuberculosis-related mortality (0% vs. 5.5%, p = 0.002). Rates of treatment failure, relapse, and acquired drug resistance were similar between the two groups. Forty-four percent of patients who received self-administered therapy had risk factors for nonadherence and should have been assigned to directly observed therapy. We conclude that treatment plans that emphasize directly observed therapy from the start of therapy have the greatest success in improving tuberculosis treatment outcomes.