Synthesis of 4'-Substituted Carbocyclic Uracil Derivatives and Their Monophosphate Prodrugs as Potential Antiviral Agents.

Over the past decades, both 4'-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4'-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A/B viruses and norovirus.

High Seroprevalence of Hepatitis B and C Virus Infections among Pregnant Women Attending Antenatal Clinic in Borumeda General Hospital, Northeast Ethiopia.

Background: Viral hepatitis are considered as the cause of solemn health problem for the human kind, particularly among pregnant women in the 21th century. Therefore, this study is aimed at determining the seroprevalence of HBV and HCV infection among pregnant women attending at Borumeda General Hospital, Dessie, Northeast Ethiopia. Methods: An institution-based cross-sectional study was conducted at Borumeda General Hospital from April to May, 2020. A consecutive total of 124 pregnant women who were attending at the antenatal clinic (ANC) of the hospital were included. A structured questionnaire was used to assess the associated factors and some sociodemographic characteristics. Five milliliters of venous blood was collected from each study participant, and a laboratory test using a rapid HBsAg and anti-HCV kit was done. The data were analyzed using SPSS software version 22. Results: The mean age of the study subjects was 25.81 (±5.967) years. The overall seroprevalence of either HBV or HCV infections among the study participants was 14 (11.3%). HBsAg and anti-HCV were positive among 10 (8.1%) and 4 (3.2%) study participants, respectively. There was no coinfection result between HBV and HCV among pregnant women. Pregnant women who had abortion history [AOR 5.723; 95% CI 1.100-29.785, P value = 0.038] and hospitalization history with IV medication [AOR 6.939; 95% CI 1.017-47.322, P value = 0.048] exhibited statistically significant association with HBV infection. Conclusions: Seroprevalence of HBV and HCV infections among pregnant women was high, and the rate of HBV particularly can be considered in the high endemic category of the WHO classification scheme. Continuous screening of pregnant mothers, provision of hepatitis B vaccine for females at the child-bearing age, and health education to create awareness about HBV and HCV should be implemented.

Sustained Impact of the Coronavirus Disease 2019 Pandemic on Hepatitis C Virus Treatment Initiations in the United States.

BACKGROUND: Recent reports indicated declines in hepatitis C virus (HCV) testing during the first half of 2020 in the United States due to coronavirus disease 2019 (COVID-19), but the longer-term impact on HCV testing and treatment is unclear. METHODS: We obtained monthly state-level volumes of HCV antibody, RNA and genotype testing, and HCV treatment initiation, stratified by age and gender, spanning January 2019 until December 2020 from 2 large national laboratories. We performed segmented regression analysis for each state from a mixed-effects Poisson regression model with month as the main fixed predictor and state as a random intercept. RESULTS: During the pre-COVID-19 period (January 2019-March 2020), monthly HCV antibody and genotype tests decreased slightly whereas RNA tests and treatment initiations remained stable. Between March and April 2020, there were declines in the number of HCV antibody tests (37% reduction, P < .001), RNA tests (37.5% reduction, P < .001), genotype tests (24% reduction, P = .023), and HCV treatment initiations (31%, P < .001). Starting April 2020 through the end of 2020, there were significant increases in month-to-month HCV antibody (P < .001), RNA (P = .035), and genotype tests (P = .047), but only antibody testing rebounded to pre-COVID-19 levels. HCV treatment initiations remained low after April 2020 throughout the remainder of the year. CONCLUSIONS: HCV testing and treatment dropped by >30% during April 2020 at the start of the COVID-19 pandemic, but although HCV testing increased again later in 2020, HCV treatment rates did not recover. Efforts should be made to link HCV-positive patients to treatment and revitalize HCV treatment engagement by healthcare providers.

Hepatitis C Elimination During a Global Pandemic: A Case Study of Resilience in Action.

Until the COVID-19 pandemic, San Francisco's hepatitis C virus (HCV) elimination initiative, End Hep C SF, was expanding and refining HCV testing and treatment strategies citywide, making progress toward local HCV elimination goals. Although a shelter-in-place health order issued in March 2020 categorized HCV testing as an "essential service," most HCV testing and treatment immediately stopped until COVID-19-safe protocols could be implemented. During the 14 months of pandemic-related organizational closures, End Hep C SF transitioned to a 100% virtual model, maintaining regularly scheduled meetings. Community-based HCV antibody testing decreased 80% from February to April 2020, and HCV treatment initiation also decreased, although both services started to rebound in mid-to-late 2020, partially as a result of End Hep C SF collaborations. End Hep C SF service providers, clinicians, and advocates reported that the continuous communication and common agenda of End Hep C SF-2 principles of the collective impact initiative-served as a familiar touchpoint and helpful source of information during this isolating and uncertain time. Ultimately, End Hep C SF allowed us to continue HCV elimination strategies through 6 lessons learned: maintaining HCV treatment access through telehealth and mobile services; leveraging research studies that provided HCV testing and treatment; offering HCV screening and linkage to care in tandem with COVID-19-related initiatives; being flexible and inventive, such as administering HCV treatment to residents of shelter-in-place hotels; establishing a data dashboard to track HCV testing and treatment; and relying on partnerships to solve problems and avoid burnout.

Seroprevalence of hepatitis B and C viruses in moderate and severe COVID-19 inpatients: A cross-sectional study at a referral center in Mexico.

INTRODUCTION AND OBJECTIVES: The emergence of SARS-CoV-2, which causes the coronavirus disease (COVID-19) has caused a great impact on healthcare systems worldwide, including hepatitis B and C viruses screening and elimination programs. The high number of COVID-19 hospitalizations represent a great opportunity to screen patients for hepatitis B virus (HBV) and hepatitis C virus (HCV), which was the aim of this study. MATERIAL AND METHODS: Cross-sectional, retrospective study performed between April 2020 and 20201 at a referral center in Mexico dedicated to the care of adults with severe/critical COVID-19. We retrieved clinical, demographic, and laboratory results from each patient´s medical records, including antibodies against HCV (anti-HCV), HBV surface antigen (HBsAg), antibodies against the HBV core antigen (anti-HBcAg), and antibodies against HBsAg (anti-HBsAg). RESULTS: Out of 3620 patients that were admitted to the hospital, 24 (0.66%), 4 (0.11%), and 72 (1.99%) tested positive for anti-HCV, HBsAg, and anti-HBcAg, respectively. Of all seronegative patients, 954 (27%) had undetectable anti-HBsAg and 401 (12%) had anti-HBsAg at protective levels. Blood transfusion was the most relevant risk factor. Only 9.7% of the anti-HBc positive, 25% of the HBsAg positive, and 52% of the anti-HCV positive were aware of their serological status. CONCLUSIONS: In this study we found a prevalence of anti-HCV of 0.66%, HBsAg in 0.11%, and isolated anti-HBcAg in 1.99%. We also found that HBV vaccination coverage has been suboptimal and needs to be reinforced. This study gave us a trustworthy insight of the actual seroprevalence in Mexico, which can help provide feedback to the Hepatitis National Elimination Plan.

Optimized cell systems for the investigation of hepatitis C virus E1E2 glycoproteins.

Great strides have been made in understanding and treating hepatitis C virus (HCV) thanks to the development of various experimental systems including cell-culture-proficient HCV, the HCV pseudoparticle system and soluble envelope glycoproteins. The HCV pseudoparticle (HCVpp) system is a platform used extensively in studies of cell entry, screening of novel entry inhibitors, assessing the phenotypes of clinically observed E1 and E2 glycoproteins and, most pertinently, in characterizing neutralizing antibody breadth induced upon vaccination and natural infection in patients. Nonetheless, some patient-derived clones produce pseudoparticles that are either non-infectious or exhibit infectivity too low for meaningful phenotyping. The mechanisms governing whether any particular clone produces infectious pseudoparticles are poorly understood. Here we show that endogenous expression of CD81, an HCV receptor and a cognate-binding partner of E2, in producer HEK 293T cells is detrimental to the infectivity of recovered HCVpp for most strains. Many HCVpp clones exhibited increased infectivity or had their infectivity rescued when they were produced in 293T cells CRISPR/Cas9 engineered to ablate CD81 expression (293TCD81KO). Clones made in 293TCD81KO cells were antigenically very similar to their matched counterparts made parental cells and appear to honour the accepted HCV entry pathway. Deletion of CD81 did not appreciably increase the recovered titres of soluble E2 (sE2). However, we did, unexpectedly, find that monomeric sE2 made in 293T cells and Freestyle 293-F (293-F) cells exhibit important differences. We found that 293-F-produced sE2 harbours mostly complex-type glycans whilst 293T-produced sE2 displays a heterogeneous mixture of both complex-type glycans and high-mannose or hybrid-type glycans. Moreover, sE2 produced in 293T cells is antigenically superior; exhibiting increased binding to conformational antibodies and the large extracellular loop of CD81. In summary, this work describes an optimal cell line for the production of HCVpp and reveals that sE2 made in 293T and 293-F cells are not antigenic equals. Our findings have implications for functional studies of E1E2 and the production of candidate immunogens.