2D to 3D Reconstruction of Boron-Linked Covalent-Organic Frameworks.

The transformation of two-dimensional (2D) covalent-organic frameworks (COFs) into three-dimensions (3D) is synthetically challenging, and it is typically addressed through interlayer cross-linking of alkene or alkyne bonds. Here, we report the first example of the chemical reconstruction of a 2D COF to a 3D COF with a complete lattice rearrangement facilitated by base-triggered boron hybridization. This chemical reconstruction involves the conversion of trigonal boronate ester linkages to tetrahedral anionic spiroborate linkages. This transformation reticulates the coplanar, closely stacked square cobalt(II) phthalocyanine (PcCo) units into a 3D perpendicular arrangement. As a result, the pore size of COFs expands from 2.45 nm for the initial 2D square lattice (sql) to 3.02 nm in the 3D noninterpenetrated network (nbo). Mechanistic studies reveal a base-catalyzed boronate ester protodeboronation pathway for the formation of the spiroborate structure.

Preferences and feasibility of long-acting technologies for treatment of hepatitis C virus in low- and middle-income countries: A survey of providers and policymakers.

Long-acting technologies (LATs) for hepatitis C virus (HCV) are under development as a strategy to improve linkage to care, treatment adherence and outcomes. We conducted a survey of HCV treatment prescribers and HCV policymakers in low- and middle-income countries (LMICs) regarding acceptability and feasibility of HCV LATs. We included one-time intramuscular injection, subdermal implant and transdermal patch as potential LAT options. We surveyed participants regarding optimal health system and patient characteristics, concerns, potential barriers, overall feasibility and preferences for HCV LAT as compared to daily oral medication. Overall, 122 providers and 50 policymakers from 42 LMICs completed the survey. Among providers, 93% (113/122) expressed willingness to prescribe LAT and 72% (88/120) of providers preferred LAT if provided at comparable efficacy, safety and cost as current oral treatments. Of providers preferring HCV LAT to daily oral medication, 67% (59/88) preferred injection, 24% (21/88) preferred patch and 9% (8/88) preferred implant. Only 20% (24/122) would prescribe LAT if it were more costly than oral treatment. In regression analysis, no provider characteristics were associated with preference for LAT over oral treatment. Policymakers reported high likelihood that LAT would be included in treatment guidelines (42/50; 84%) and national drug formularies (39/50; 78%) if efficacy, safety and cost were similar to oral treatment. HCV LATs could advance progress to HCV elimination in LMICs by diversifying treatment options to improve treatment coverage and outcomes. Provider preferences from LMICs are a critical consideration in the development of HCV LATs to ensure its early and equitable availability in LMICs.

Hepatitis C Elimination in Rwanda: Progress, Feasibility, and Economic Evaluation.

OBJECTIVES: In 2018, Rwanda launched a national program to eliminate the hepatitis C virus (HCV). We aim to assess the impact of the program to date and identify strategies to achieve the World Health Organization's HCV elimination goals by 2030. METHODS: We developed a microsimulation model to simulate Rwanda's HCV epidemic from 2015 through 2050 and evaluated temporal trends in HCV infection, prevalence, mortality, and the total cost of care for scenarios that could achieve HCV elimination by 2030. RESULTS: Between 2018 and 2022, over 7 million people were screened for HCV, and 60 000 were treated. The study projected that Rwanda could achieve HCV elimination as early as 2027. A feasible strategy of an annual screening rate of 15% and a treatment rate of 100% would achieve all World Health Organization elimination goals by 2028, requiring screening an additional 4 million people and treating 23 900 patients by 2030. The elimination strategy costs $25 million for screening and diagnosis and $21 million for treatment from 2015 to 2050. The national program would avert 4900 hepatocellular carcinoma cases and 6700 HCV-related deaths and save the health system $25.33 million from 2015 to 2050. CONCLUSIONS: Rwanda is poised to become one of the first countries in the world to eliminate HCV. Rwanda's program serves as a blueprint for other countries in the African region. By rapid screening and treatment scale-up (eg, by leveraging HIV platforms) and by drug price negotiations, HCV elimination is not only feasible but can be cost-saving in low-income settings.

Progress towards elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission update.

The top 20 highest burdened countries (in disability-adjusted life years) account for more than 75% of the global burden of viral hepatitis. An effective response in these 20 countries is crucial if global elimination targets are to be achieved. In this update of the Lancet Gastroenterology & Hepatology Commission on accelerating the elimination of viral hepatitis, we convene national experts from each of the top 20 highest burdened countries to provide an update on progress. Although the global burden of diseases is falling, progress towards elimination varies greatly by country. By use of a hepatitis elimination policy index conceived as part of the 2019 Commission, we measure countries' progress towards elimination. Progress in elimination policy has been made in 14 of 20 countries with the highest burden since 2018, with the most substantial gains observed in Bangladesh, India, Indonesia, Japan, and Russia. Most improvements are attributable to the publication of formalised national action plans for the elimination of viral hepatitis, provision of publicly funded screening programmes, and government subsidisation of antiviral treatments. Key themes that emerged from discussion between national commissioners from the highest burdened countries build on the original recommendations to accelerate the global elimination of viral hepatitis. These themes include the need for simplified models of care, improved access to appropriate diagnostics, financing initiatives, and rapid implementation of lessons from the COVID-19 pandemic.

Direct-acting antiviral therapies for hepatitis C infection: global registration, reimbursement, and restrictions.

Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection have delivered high response rates (>95%) and simplified the management of HCV treatment, permitting non-specialists to manage patients without advanced liver disease. We collected and reviewed global data on the registration and reimbursement (government subsidised) of HCV therapies, including restrictions on reimbursement. Primary data collection occurred between Nov 15, 2021, and July 24, 2023, through the assistance of a global network of 166 HCV experts. We retrieved data for 160 (77%) of 209 countries and juristrictions. By mid-2023, 145 (91%) countries had registered at least one of the following DAA therapies: sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-voxilaprevir, glecaprevir-pibrentasvir, sofosbuvir-daclatasvir, or sofosbuvir. 109 (68%) countries reimbursed at least one DAA therapy. Among 102 low-income and middle-income countries (LMICs), 89 (87%) had registered at least one HCV DAA therapy and 53 (52%) reimbursed at least one DAA therapy. Among all countries with DAA therapy reimbursement (n=109), 66 (61%) required specialist prescribing, eight (7%) had retreatment restrictions, seven (6%) had an illicit drug use restriction, five (5%) had an alcohol use restriction, and three (3%) had liver disease restrictions. Global access to DAA reimbursement remains uneven, with LMICs having comparatively low reimbursement compared with high-income countries. To meet WHO goals for HCV elimination, efforts should be made to assist countries, particularly LMICs, to increase access to DAA reimbursement and remove reimbursement restrictions-especially prescriber-type restrictions-to ensure universal access.

Prevention, testing, and treatment interventions for hepatitis B and C in refugee populations: results of a scoping review.

BACKGROUND AND AIMS: Refugees are at higher risk for hepatitis B (HBV) and hepatitis C (HCV), but often face unique healthcare barriers to vaccination, testing, and treatment. This scoping review aimed to identify and characterize HBV and HCV prevention and care services serving refugee populations globally. METHODS: A literature search was conducted on Embase, Cochrane, and PubMed databases. Research studies published in English between January 2010 to July 2022 describing an HBV or HCV prevention, testing, or treatment intervention for refugees were included. RESULTS: There were a total of 69 articles reporting viral hepatitis prevalence, implementation of services, or economic modelling. Of the 38 implementation studies, 14 were stand-alone HBV and/or HCV interventions, while 24 studies included HBV and/or HCV in an intervention targeting multiple infectious diseases and/or parasitic infections. Interventions commonly included a testing (n = 30) or referral (n = 24) component. Frequently reported features to promote program accessibility included bilingual services (n = 25), community partnerships (n = 21), and multidisciplinary staff members (n = 18), such as cultural and/or linguistic mediators, community health workers, community health leaders, lay health workers, local health staff, members of the refugee community, and social workers. The most commonly reported challenge was the transience of refugees (n = 5). Twenty studies noted funding sources, of which twelve reported governmental funding (not including national health insurance) and eight reported that refugees received national health insurance. CONCLUSIONS: This is the first scoping review to characterize the types of hepatitis prevention, screening, and treatment interventions serving refugee populations globally. Published experiences of HBV and HCV services for refugee populations remain limited. Additional efforts are needed to disseminate models of hepatitis interventions for refugees to ensure access to care for this key population. To achieve hepatitis elimination globally, best practices must be identified and shared to expand access to hepatitis services for refugee populations.

The impact of COVID-19 on hepatitis B and C virus prevention, diagnosis, and treatment in Bangladesh compared with Japan and the global perspective.

AIM: This study aimed to assess the effect of COVID-19 on hepatitis-related services in Bangladesh and compared the situation with same study conducted in Japan and globally. METHODS: We conducted an online cross-sectional questionnaire survey among the clinicians of four societies associated with liver disease in Bangladesh from October to December 2022. The questionnaire included the same questions as a survey conducted in Japan and globally. RESULTS: A total of 83 clinicians from 8 divisions in Bangladesh participated; 66.3% were heads of departments/institutions. Except for HCV treatment initiation, more than 30% of clinicians reported a 76-99% decline in all services. Compared to Japan and the global survey, there was a significantly higher decline in all HBV and HCV services in Bangladesh. To resume services back to pre-COVID-19 levels, Patient anxiety and fear (Bangladesh Survey: 80.7% vs Japan Survey: 67.4% vs Global Survey: 37.9%, p < 0.0001), loss of space due to COVID-19 (Bangladesh Survey: 63.9% vs Japan Survey: 34.7% vs Global Survey: 19.4%, p < 0.0001) were the main challenges. As part of the mitigation strategy, usage of telemedicine (Bangladesh Survey: 83.1% vs. Japan Survey: 67.3% vs Global Survey: 78.6% p < 0.0001), COVID-19 benefits, such as increased laboratory testing platforms (Bangladesh Survey: 77.1% vs Japan Survey: 17.9% vs Global Survey: 41.8%, p < 0.0001) was reported significantly higher in Bangladesh than in Japan and global survey. CONCLUSION: All the services-related to HBV and HCV were highly affected during greatest impact month of COVID-19 in Bangladesh and the decline level was higher than Japan and global survey. Repeated countermeasures of COVID-19 and constrained healthcare-system were the probable reasons in Bangladesh. Positive impact resulting from COVID-19 countermeasures should be utilized in the national hepatitis program in Bangladesh.

Tools Needed to Support Same-day Diagnosis and Treatment of Current Hepatitis C Infection.

Current HCV prevention efforts and treatment rates must improve for the United States (U.S.) to achieve WHO global elimination targets by 2030[1]. The current multi-day diagnosis and treatment paradigm for hepatitis C (HCV) infection leads to significant loss in the cascade of care, resulting in far fewer patients receiving treatment with direct acting antiviral agents (DAAs) than those diagnosed with HCV infection [2,3]. To achieve HCV elimination, a paradigm shift in access to HCV treatment is needed from current multi-day testing and treatment algorithms to same day diagnosis and treatment. This shift will require new tools, such as FDA-approved, CLIA-waived point-of-care (POC) antigen or nucleic acid tests (NAT) for HCV and HBV and NAT for HIV that do not require venous blood. Such a shift will also require better utilization of existing resources, expanding access to HCV treatment through availability of onsite treatment, removal of payer barriers to approval, adoption of minimal monitoring approaches during treatment, expanded access to available POC tests, and available specialist referral networks for patients who fail initial therapy, have advanced liver fibrosis, or have co-incident HIV or HBV infection. A same-day diagnosis and treatment paradigm will substantially contribute to HCV elimination by improving treatment rates for those diagnosed with HCV infection and expanding access to treatment in settings where patients have brief encounters with healthcare.

Strategies for Removal of Barriers to Hepatitis C Elimination in Sub-Saharan Africa.

Hepatitis C virus (HCV) infection is a major global health threat, with serious consequences including liver cirrhosis and cancer. Despite efforts to combat HCV, an estimated 1.5 million new infections occur each year and HCV was the sixth leading cause of death in 2017. Nevertheless, political leaders are increasingly interested in the fight against HCV, and the achievements of countries such as Rwanda, Egypt, India, Mongolia, Pakistan, Georgia, and Ukraine have given hope that the elimination plan to reduce new infections to 90% and mortality to 65% by 2030 is possible. It is true that some African countries can attest to the difficulty of operationalizing the HCV program with expensive testing platforms and HCV drugs that few could afford in the past, let alone the logistics involved, given that active case detection is an asset for HCV elimination. The inability to add direct-acting antivirals (DAAs) to the national essential drug list and negotiate DAA cost subsidies remains a major challenge in Africa. The lessons learned from implementing and scaling up the human immunodeficiency virus program can provide a strong framework to deliver comprehensive HCV services. We present the strategies used by some African countries to move toward HCV elimination, describe the challenges they have faced, and suggest realistic solutions.

An Assessment of National Strategic Action Plans for Viral Hepatitis Elimination, 2016-2021.

In 2016, the World Health Organization (WHO) released the Global Health Sector Strategy (GHSS) setting goals for global hepatitis elimination. To inform new or revised viral hepatitis national strategic action plans (NSAPs) for 2022-2030, NSAPs developed during 2016-2021 were assessed for alignment with the WHO GHSS. Country NSAPs were assessed to determine if they included components in the 2016 GHSS. Of 55 country NSAPs, 19 (35%) did not include hepatitis B and C virus elimination goals, only 18 (33%) included targets for needles and syringes for persons who inject drugs, and 21 (38%) had a national budget or financing plan for hepatitis activities. Gaps identified indicate need for technical support in NSAP development.

Hepatitis C Elimination in Moldova Is Feasible and Cost-Saving: A Modeling Study.

BACKGROUND: Moldova, an upper-middle-income country in Eastern Europe, is facing a high burden of hepatitis C virus (HCV). Our objective was to assist the National Agency of Public Health of Moldova in planning to achieve the World Health Organization's HCV elimination goals by 2030. METHODS: This study adapted a previously developed microsimulation model to simulate the HCV epidemic in Moldova from 2004 to 2050. Model outcomes included temporal trends in HCV infection, prevalence, mortality, and total cost of care, including screening and treatment. We evaluated scenarios that could eliminate HCV by 2030. RESULTS: Multiple strategies could lead to HCV elimination in Moldova by 2030. A realistic scenario of a 20% annual screening and 80% treatment rate would require 2.75 million individuals to be screened and 65 000 treated by 2030. Compared to 2015, this program will reduce HCV incidence by 98% and HCV-related deaths by 72% in 2030. Between 2022 and 2030, this strategy would cost $17.5 million for HCV screening and treatment. However, by 2050, the health system would save >$85 million compared to no investment in elimination efforts. CONCLUSIONS: HCV elimination in Moldova is feasible and can be cost saving, but requires resources to scale HCV screening and treatment.

Dynamic and Persistent Cyclochirality in Hydrogen-Bonded Derivatives of Medium-Ring Triamines.

Cyclic triureas derived from 1,4,7-triazacyclononane (TACN) were synthesized; X-ray crystallography showed a chiral bowl-like conformation with each urea hydrogen-bonded to its neighbor with uniform directionality, forming a "cyclochiral" closed loop of hydrogen bonds. Variable-temperature 1H NMR, 1H-1H exchange spectroscopy, Eyring analysis, computational modeling, and studies in various solvents revealed that cyclochirality is dynamic (ΔG‡25°C = 63-71 kJ mol-1 in noncoordinating solvents), exchanging between enantiomers by two mechanisms: bowl inversion and directionality reversal, with the former subject to a slightly smaller enantiomerization barrier. The enantiomerization rate substantially increased in the presence of hydrogen-bonding solvents. Population of only one of the two cyclochiral hydrogen-bond directionalities could be induced by annulating one ethylene bridge with a trans-cyclohexane. Alternatively, enantiomerization could be inhibited by annulating one ethylene bridge with a cis-cyclohexane (preventing bowl inversion) and replacing one urea function with a formamide (preventing directionality reversal). Combining these structural modifications resulted in an enantiomerization barrier of ΔG‡25°C = 93 kJ mol-1, furnishing a planar-chiral, atropisomeric bowl-shaped structure whose stereochemical stability arises solely from its hydrogen-bonding network.

Reflex Hepatitis C Virus Viral Load Testing Following an Initial Positive Hepatitis C Virus Antibody Test: A Global Systematic Review and Meta-analysis.

BACKGROUND: Many people who have a positive hepatitis C virus (HCV) antibody (Ab) test never receive a confirmatory HCV RNA viral load (VL) test. Reflex VL testing may help address this problem. We undertook a systematic review to evaluate the effectiveness of reflex VL testing compared with standard nonreflex approaches on outcomes across the HCV care cascade. METHODS: We searched 4 databases for studies that examined laboratory-based reflex or clinic-based reflex VL testing approaches, with or without a nonreflex comparator, and had data on the uptake of HCV RNA VL test and treatment initiation and turnaround time between Ab and VL testing. Both laboratory- and clinic-based reflex VL testing involve only a single clinic visit. Summary estimates were calculated using random-effects meta-analyses. RESULTS: Fifty-one studies were included (32 laboratory-based and 19 clinic-based reflex VL testing). Laboratory-based reflex VL testing increased HCV VL test uptake versus nonreflex testing (RR: 1.35; 95% CI: 1.16-1.58) and may improve linkage to care among people with a positive HCV RNA test (RR: 1.47; 95% CI: .81-2.67) and HCV treatment initiation (RR: 1.03; 95% CI: .46-2.32). The median time between Ab and VL test was <1 day for all laboratory-based reflex studies and 0-5 days for 13 clinic-based reflex testing. CONCLUSIONS: Laboratory-based and clinic-based HCV reflex VL testing increased uptake and reduced time to HCV VL testing and may increase HCV linkage to care. The World Health Organization now recommends reflex VL testing as an additional strategy to promote access to HCV VL testing and treatment. CLINICAL TRIALS REGISTRATION: PROSPERO CRD42021283822.

Hepatitis C virus seroprevalence, testing, and treatment capacity in public health facilities in Ghana, 2016-2021; A multi-centre cross-sectional study.

The current burden of Hepatitis C virus infection and the availability of HCV-related services in Ghana are not well described. Previous estimates on HCV seroprevalence in the country are outdated. This study investigated the HCV seroprevalence and testing and treatment capacity in Ghana. A multi-centre cross-sectional study was conducted in which laboratory and blood bank registers from 17 public healthcare institutions in Ghana were reviewed. A survey on cost and availability of HCV-related testing and treatment was also performed. Crude and pooled estimates of HCV seroprevalence, frequency and median cost of available diagnostic tests and medicines were described. The crude HCV seroprevalence was 2.62% (95% CI 2.53-2.72) and the pooled estimate was 4.58% (95% CI 4.06-5.11) among 103,609 persons tested in laboratories. Age (OR 1.02 95% CI 1.01-1.02) and male sex (OR 1.26 95% CI 1.08-1.48) were predictors of a positive anti-HCV RDT test. Northern administrative regions in Ghana had the highest HCV seroprevalence ranging from 8.3-14.4%. Among 55, 458 potential blood donors, crude HCV seroprevalence was 3.57% (95% CI 3.42-3.72). Testing was through Rapid Diagnostic Test (RDT) kits in most facilities, and only 2 of 17 centres were performing HCV RNA testing. The median cost of an anti-HCV RDT test was $0.97 (0-1.61) and $3.23 (1.61-7.58) for persons with and without government health insurance respectively. The median cost of a 12-week course of the pan-genotypic direct-acting antiviral therapy sofosbuvir-daclatasvir was $887.70. In conclusion, there are significant regional differences in HCV burden across Ghana. Limited access to and cost of HCV RNA and DAA therapy hinders testing and treatment capability, and consequently HCV elimination efforts. A national HCV program supported with a sustainable financing plan is required to accelerate HCV elimination in Ghana.

Overcome Health Inequities to Eliminate Viral Hepatitis.

This Viewpoint outlines the progress made toward eliminating hepatitis B and C but emphasizes the work that remains to prioritize diagnosis and treatment of populations disproportionately affected by viral hepatitis, including ensuring that there are systems in place to treat those infected and care for those at risk.

Prevention of Hepatocellular Carcinoma (HCC). White Paper of the Texas Collaborative Center for Hepatocellular Cancer (TeCH) Multi-stakeholder Conference.

BACKGROUND & AIMS: Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. The Cancer Prevention and Research Institute of Texas has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate HCC research, education, and advocacy activities with the overall goal of reducing HCC mortality in Texas through coordination, collaboration, and advocacy. METHODS: On September 17, 2022, TeCH co-sponsored a multi-stakeholder conference on HCC with the Baker Institute Center for Health and Biosciences. This conference was attended by HCC researchers, policy makers, payers, members from pharmaceutical industry and patient advocacy groups in and outside of Texas. This report summarizes the results of the conference. RESULTS: The goal of this meeting was to identify different strategies for preventing HCC and evaluate their readiness for implementation. CONCLUSIONS: We call for a statewide (1) viral hepatitis elimination program; (2) program to increase nonalcoholic steatohepatitis and obesity awareness; (3) research program to develop health care models that integrate alcohol associated liver disease treatment and treatment for alcohol use disorder; and (4) demonstration projects to evaluate the effectiveness of identifying and linking patient with advanced fibrosis and cirrhosis to clinical care.

Experimental Confirmation of a Predicted Porous Hydrogen-Bonded Organic Framework.

Hydrogen-bonded organic frameworks (HOFs) with low densities and high porosities are rare and challenging to design because most molecules have a strong energetic preference for close packing. Crystal structure prediction (CSP) can rank the crystal packings available to an organic molecule based on their relative lattice energies. This has become a powerful tool for the a priori design of porous molecular crystals. Previously, we combined CSP with structure-property predictions to generate energy-structure-function (ESF) maps for a series of triptycene-based molecules with quinoxaline groups. From these ESF maps, triptycene trisquinoxalinedione (TH5) was predicted to form a previously unknown low-energy HOF (TH5-A) with a remarkably low density of 0.374 g cm-3 and three-dimensional (3D) pores. Here, we demonstrate the reliability of those ESF maps by discovering this TH5-A polymorph experimentally. This material has a high accessible surface area of 3,284 m2 g-1 , as measured by nitrogen adsorption, making it one of the most porous HOFs reported to date.