An eco-friendly and cost-effective HPTLC method for quantification of COVID-19 antiviral drug and co-administered medications in spiked human plasma.

The coronavirus-2 has led to a global pandemic of COVID-19 with an outbreak of severe acute respiratory syndrome leading to worldwide quarantine measures and a rise in death rates. The objective of this study is to propose a green, sensitive, and selective densitometric method to simultaneously quantify remdesivir (REM) in the presence of the co-administered drug linezolid (LNZ) and rivaroxaban (RIV) in spiked human plasma. TLC silica gel aluminum plates 60 F254 were used as the stationary phase, and the mobile phase was composed of dichloromethane (DCM): acetone (8.5:1.5, v/v) with densitometric detection at 254 nm. Well-resolved peaks have been observed with retardation factors (Rf) of 0.23, 0.53, and 0.72 for REM, LNZ, and RIV, respectively. A validation study was conducted according to ICH Q2 (R1) Guidelines. The method was rectilinear over the concentration ranges of 0.2-5.5 µg/band, 0.2-4.5 µg/band and 0.1-3.0 µg/band for REM, LNZ and RIV, respectively. The sensitivities of REM, LIN, and RIV were outstanding, with quantitation limits of 128.8, 50.5, and 55.8 ng/band, respectively. The approach has shown outstanding recoveries ranging from 98.3 to 101.2% when applied to pharmaceutical formulations and spiked human plasma. The method's greenness was assessed using Analytical Eco-scale, GAPI, and AGREE metrics.

Therapeutic effectiveness analysis of tenofovir alafenamide and tenofovir disoproxil fumarate on the treatment for chronic hepatitis B.

To explore the therapeutic effectiveness of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on the treatment for chronic hepatitis B (CHB). Retrospectively analyzing 241 cases of chronic hepatitis B patients admitted to our hospital from January 2020 to December 2021, they were divided into a TAF group of 180 cases and a TDF group of 61 cases. The liver function, serum virus markers, clinical efficacy, adverse reactions and cost-effectiveness ratio (CER) analysis of 2 groups were compared. Two groups of patients had no statistically significant difference in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) before treatment. After treatment, the levels of ALT, AST and TBIL were lower than before treatment in both groups (P < .05), but the inter-group difference was not statistically significant (P > .05). After treatment, Hepatitis B surface antigen (HBsAg) conversion rate and Hepatitis B virus DNA (HBV-DNA) conversion rate in the 2 groups had no statistically significant difference. After treatment, the difference in total clinical cure rate between the 2 groups has no statistical significance (P > .05), adverse reactions rate of TAF group was lower than that of TDF group (P < .05). The drug cost median of TAF group was higher than that of TDF (P < .05), but Cost-effectiveness analysis showed the CER of TAF group was similar of TDF group. TAF or TDF therapy can both improve liver function and promote recovery in patients with CHB, achieving the goal of treatment. TAF have more cost but have similar CER to TDF. Moreover, TAF therapy has a higher safety profile.

The politics and governance of drug production in public-private partnerships: Brazil's response to hepatitis C.

The local manufacture of advanced pharmaceutical products has been a long-standing objective of health and industry policy in many developing countries, including in Latin America. This strategy has been applied to fight epidemics such as HIV/AIDS, malaria, and the COVID-19 pandemic. However, we still know little about the politics and governance that enable such arrangements, especially when there is no consent from the originator company. This study focuses on the case of Brazil, a country that is well-known for its health-industry policy, which includes the local production of direct-acting antivirals (DAAs), a new treatment for hepatitis C. We seek to explain the factors that have contributed to Brazil's successful production of generic versions of DAAs, and, later, to the decision by the Ministry of Health (MoH) to procure drugs from multinational pharmaceutical companies rather than from local laboratories. A lack of support for domestic production by important stakeholders, the patent holder's attempt to block domestic production and the MoH's adoption of more modern treatment guidelines under a different procurement logic all created an unfavourable environment for local production and procurement of DAAs. Our study draws implications for middle-income countries that wish to produce drugs domestically without voluntary license agreements.

Phenotypic assessment of antiviral activity for spiro-annulated oxepanes and azepenes.

Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure-activity relationships for data-driven drug discovery. Here we present a primary assessment of antiviral activity of spiro-annulated derivatives of seven-membered heterocycles, oxepane and azepane, in phenotypic assays against viruses with different genomes, virion structures, and genome realization schemes: orthoflavivirus (tick-borne encephalitis virus, TBEV), enteroviruses (poliovirus, enterovirus A71, echovirus 30), adenovirus (human adenovirus C5), hantavirus (Puumala virus). Hit compounds inhibited reproduction of adenovirus C5, the only DNA virus in the studied set, in the yield reduction assay, and did not inhibit reproduction of RNA viruses.

A cost analysis of a simplified model for HCV screening and treatment at a tertiary hospital in Zimbabwe.

BACKGROUND: The treatment of chronic hepatitis C virus (HCV) infection using directly acting antivirals was recently adopted in the treatment guidelines of Zimbabwe. The objectives of this study were to design a simplified model of HCV care and estimate the cost of screening and treatment of hepatitis C infection at a tertiary hospital in Zimbabwe. METHODS: We developed a model of care for HCV using WHO 2018 guidelines for the treatment of HCV infection and expert opinion. We then performed a micro-costing to estimate the costs of implementing the model of care from the healthcare sector perspective. Deterministic and probabilistic sensitivity analyses were performed to explore the impact of uncertainty in input parameters on the estimated total cost of care. RESULTS: The total cost of screening and treatment was estimated to be US$2448 (SD=$290) per patient over a 12-week treatment duration using sofosbuvir/velpatasvir. The cost of directly acting antivirals contributed 57.5% to the total cost of care. The second largest cost driver was the cost of diagnosis, US$819, contributing 34.6% to the total cost of care. CONCLUSION: Screening and treatment of HCV-infected individuals using directly acting antivirals at a tertiary hospital in Zimbabwe may require substantial financial resources.

Noninvasive assessment of liver fibrosis can predict clinical outcomes at late follow-up after a sustained virological response in HCV patients?

OBJECTIVES: The primary objective was to evaluate Liver-Related Events (LREs), including hepatic decompensation (ascites, hemorrhagic varices and encephalopathy) and Hepatocellular Carcinoma (HCC), as well as changes in liver stiffness during the follow-up period among patients who achieved a Sustained Virological Response (SVR) after treatment for chronic Hepatitis C Virus (HCV) infection. METHODS: A total of 218 patients with HCV were treated, and those who achieved an SVR were followed up for 3-years. Transient Elastography (TE) using FibroScan® was performed at various time points: before treatment, at the end of treatment, at 6-months post-treatment, at 1-year post-treatment, at 2-years post-treatment, and at 3-years post-treatment. RESULTS: At 6-months post-treatment, a Liver Stiffness Measurement (LSM) cutoff of > 19 KPa was identified, leading to a 14.5-fold increase in the hazard of negative outcomes, including decompensation and/or HCC. The analysis of relative changes in liver stiffness between pre-treatment and 6-months posttreatment revealed that a reduction in LSM of -10 % was associated with a -12 % decrease in the hazard of decompensation and/or HCC, with this trend continuing as the LSM reduction reached -40 %, resulting in a -41 % hazard of decompensation and/or HCC. Conversely, an increase in the relative change during this period, such as an LSM increase of +10 %, led to a + 14 % increase in the hazard of decompensation. In cases where this relative change in LSM was +50 %, the hazard of decompensation increased to +92. CONCLUSION: Transient elastography using FibroScan® can be a good tool for monitoring HCV patients with SVR after treatment to predict LREs in the long term.

Assessment of effectiveness and impact of universal prophylaxis with nirsevimab for prevention of hospitalizations due to respiratory syncytial virus in infants. The NIRSE-GAL study protocol.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Lessons Learned from Model-based Economic Evaluations of COVID-19 Drug Treatments Under Pandemic Circumstances: Results from a Systematic Review.

BACKGROUND: Following clinical research of potential coronavirus disease 2019 (COVID-19) treatments, numerous decision-analytic models have been developed. Due to pandemic circumstances, clinical evidence was limited and modelling choices were made under great uncertainty. This study aimed to analyse key methodological characteristics of model-based economic evaluations of COVID-19 drug treatments, and specifically focused on modelling choices which pertain to disease severity levels during hospitalisation, model structure, sources of effectiveness and quality of life and long-term sequelae. METHODS: We conducted a systematic literature review and searched key databases (including MEDLINE, EMBASE, Web of Science, Scopus) for original articles on model-based full economic evaluations of COVID-19 drug treatments. Studies focussing on vaccines, diagnostic techniques and non-pharmaceutical interventions were excluded. The search was last rerun on 22 July 2023. Results were narratively synthesised in tabular form. Several aspects were categorised into rubrics to enable comparison across studies. RESULTS: Of the 1047 records identified, 27 were included, and 23 studies (85.2%) differentiated patients by disease severity in the hospitalisation phase. Patients were differentiated by type of respiratory support, level of care management, a combination of both or symptoms. A Markov model was applied in 16 studies (59.3%), whether or not preceded by a decision tree or an epidemiological model. Most cost-utility analyses lacked the incorporation of COVID-19-specific health utility values. Of ten studies with a lifetime horizon, seven adjusted general population estimates to account for long-term sequelae (i.e. mortality, quality of life and costs), lasting for 1 year, 5 years, or a patient's lifetime. The most often reported parameter influencing the outcome of the analysis was related to treatment effectiveness. CONCLUSION: The results illustrate the variety in modelling approaches of COVID-19 drug treatments and address the need for a more standardized approach in model-based economic evaluations of infectious diseases such as COVID-19. TRIAL REGISTRY: Protocol registered in PROSPERO under CRD42023407646.

Evaluation of a Project Integrating Financial Incentives into a Hepatitis C Testing and Treatment Model of Care at a Sexual Health Service in Cairns, Australia, 2020-2021.

BACKGROUND: Understanding the effectiveness of novel models of care in community-based settings is critical to achieving hepatitis C elimination. We conducted an evaluation of a hepatitis C model of care with financial incentives that aimed to improve engagement across the hepatitis C cascade of care at a sexual health service in Cairns, Australia. METHODS: Between March 2020 and May 2021, financial incentives were embedded into an established person-centred hepatitis C model of care at Cairns Sexual Health Service. Clients of the Service who self-reported experiences of injecting drugs were offered an AUD 20 cash incentive for hepatitis C testing, treatment initiation, treatment completion, and test for cure. Descriptive statistics were used to describe retention in hepatitis C care in the incentivised model. They were compared to the standard of care offered in the 11 months prior to intervention. RESULTS: A total of 121 clients received financial incentives for hepatitis C testing (antibody or RNA). Twenty-eight clients were hepatitis C RNA positive, of whom 92% (24/28) commenced treatment, 75% (21/28) completed treatment, and 68% (19/28) achieved a sustained virological response (SVR). There were improvements in the proportion of clients diagnosed with hepatitis C who commenced treatment (86% vs. 75%), completed treatment (75% vs. 40%), and achieved SVR (68% vs. 17%) compared to the pre-intervention comparison period. CONCLUSIONS: In this study, financial incentives improved engagement and retention in hepatitis C care for people who inject drugs in a model of care that incorporated a person-centred and flexible approach.

Cost-utility analysis of palivizumab for preventing respiratory syncytial virus in preterm neonates and infants in Colombia.

AIM: Palivizumab has proven effective in reducing hospitalizations, preventing severe illness, improving health outcomes, and reducing healthcare costs for infants at risk of respiratory syncytial virus (RSV) infection. We aim to assess the value of palivizumab in preventing RSV infection in high-risk infants in Colombia, where RSV poses a significant threat, causing severe respiratory illness and hospitalizations. METHODS: We conducted a decision tree analysis to compare five doses of palivizumab with no palivizumab. The study considered three population groups: preterm neonates (≤ 35 weeks gestational age), infants with bronchopulmonary dysplasia (BPD), and infants with hemodynamically significant congenital heart disease (CHD). We obtained clinical efficacy data from IMpact-RSV and Cardiac Synagis trials, while we derived neonatal hospitalization risks from the SENTINEL-1 study. We based hospitalization and recurrent wheezing management costs on Colombian analyses and validated them by experts. We estimated incremental cost-effectiveness ratios and performed 1,000 Monte Carlo simulations for probabilistic sensitivity analyses. RESULTS: Palivizumab is a dominant strategy for preventing RSV infection in preterm neonates and infants with BPD and CHD. Its high efficacy (78% in preventing RSV in preterm infants), the substantial risk of illness and hospitalization, and the high costs associated with hospitalization, particularly in neonatal intensive care settings, support this finding. The scatter plots and willingness-to-pay curves align with these results. CONCLUSION: Palivizumab is a cost-saving strategy in Colombia, effectively preventing RSV infection in preterm neonates and infants with BPD and CHD by reducing hospitalizations and lowering healthcare costs.

Barriers to access to hepatitis C treatment with direct-acting antivirals in people who inject drugs in the community setting.

Barriers to access to hepatitis C treatment with direct-acting antivirals in people who inject drugs in the community setting. Qualitative study with prison population. Hepatitis C (HCV) treatments with direct-acting antiviral therapy (DAA) are an easy and effective option among people who inject drugs (PWID). However, difficulties in accessing and monitoring treatment in community services and dropouts on release from prison are detected among PWID. For this reason, the aim of the study is to know the access barriers in the diagnosis and treatment of HCV in community health services. An exploratory qualitative study was carried out through semi-structured interviews with 33 PWID recruited in a pre-trial detention prison in Barcelona. The information obtained was analysed using grounded theory. Among PWID sub-population entering prison, personal barriers are related to intense drug use, lack of interest and ignorance of HCV infection and treatment, as well as being in a situation of social exclusion. In relation to health providers, they reported receiving little information, the existence of language barriers in migrants, not receiving screening and treatment proposals, and having poor interactions with some professionals. Systemic barriers were expressed related to the health system circuit being complicated, perceiving little comprehensive care and lack of community support. It is recommended to intensify prevention and treatment campaigns, promoting drug substitution programmes than current ones, improve health education, make the diagnosis and treatment process more flexible, and promote social policies and holistic care for greater coverage of the needs of PWID.

Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

Towards Greener and More Cost-efficient Biosynthesis of Pharmaceuticals and Fragrance Molecules.

Enzymes are natural catalysts which are gaining momentum in chemical synthesis due to their exquisiteselectivity and their biodegradability. However, the cost-efficiency and the sustainability of the overall biocatalytic process must be enhanced to unlock completely the potential of enzymes for industrial applications. To reach this goal, enzyme immobilization and the integration into continuous flow reactors have been the cornerstone of our research. We showed key examples of the advantages of those tools for the biosynthesis of antivirals, anticancer drugs, and valuable fragrance molecules. By combining new strategies to immobilize biocatalysts, innovative bioengineering approaches, and process development, the performance of the reactions could be boosted up to 100-fold.

Cost effectiveness of hepatitis C direct acting agents.

INTRODUCTION: Introduction of direct acting antivirals (DAA) has transformed treatment of chronic hepatitis C (HCV) and made the elimination of HCV an achievable goal set forward by World Health Organization by 2030. Multiple barriers need to be overcome for successful eradication of HCV. Availability of pan-genotypic HCV regimens has decreased the need for genotype testing but maintained high efficacy associated with DAAs. AREAS COVERED: In this review, we will assess the cost-effectiveness of DAA treatment in patients with chronic HCV disease, with emphasis on general, cirrhosis, and vulnerable populations. EXPERT OPINION: Multiple barriers exist limiting eradication of HCV, including cost to treatment, access, simplified testing, and implementing policy to foster treatment for all groups of HCV patients. Clinically, DAAs have drastically changed the landscape of HCV, but focused targeting of vulnerable groups is needed. Public policy will continue to play a strong role in eliminating HCV. While we will focus on the cost-effectiveness of DAA, several other factors regarding HCV require on going attention, such as increasing public awareness and decreasing social stigma associated with HCV, offering universal screening followed by linkage to treatment and improving preventive interventions to decrease spread of HCV.

Burden, Outcome, and Comorbidities of Extrahepatic Manifestations in Hepatitis B Virus Infections.

Hepatitis B virus (HBV) infections affect approximately 296 million people around the world, and the prevalence of any past or present HBV infection during the years 2015-2018 was as high as 4.3%. Acute HBV infection often presents with nonspecific symptoms and is usually self-limited, but 5% of patients can have persistent infections leading to chronic HBV infection and the risk of turning into chronic HBV infection is significantly higher in babies with vertical transmission (95%). Patients with chronic HBV infection are usually asymptomatic, but 15 to 40% of chronic HBV carriers develop cirrhosis and/or hepatocellular carcinoma. In addition to liver-related disorders, HBV is also associated with several extrahepatic complications, including glomerulonephritis, cryoglobulinemia, neurologic disorders, psychological manifestations, polyarthritis, and dermatologic disorders. Making the diagnosis of HBV can be challenging since patients with chronic infections can remain symptom-free for decades before developing cirrhosis or hepatocellular carcinoma, and patients with acute HBV infection may have only mild, nonspecific symptoms. Therefore, understanding how this virus causes extrahepatic complications can help clinicians consider this possibility in patients with diverse symptom presentations. The pathophysiology of these extrahepatic disorders likely involves immune-related tissue injury following immune complex formation and inflammatory cascades. In some cases, direct viral infection of extrahepatic tissue may cause a clinical syndrome. Currently, the American Association for the Study of Liver Diseases recommends treatment of chronic HBV infections with interferon therapy and/or nucleos(t)ide analogs, and this treatment has been reported to improve some extrahepatic disorders in some patients with chronic HBV infection. These extrahepatic complications have a significant role in disease outcomes and increase medical costs, morbidity, and mortality. Therefore, understanding the frequency and pathogenesis of these extrahepatic complications provides important information for both specialists and nonspecialists and may help clinicians identify patients at an earlier stage of their infection.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs.

Importance: Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. Objective: To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. Design, Setting, and Participants: This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Exposure: Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Main Outcomes and Measures: Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Results: Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. Conclusions and Relevance: The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

Hepatitis B Delta: assessment of the knowledge and practices of hepato-gastroenterologists practicing in non-academic settings in France.

BACKGROUND: Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France. OBJECTIVE: We aimed to evaluate the knowledge and practices of HGs practicing in nonacademic settings regarding HB-D. METHODS: A Google form document was sent to those HGs from May to September 2021. RESULTS: A total of 130 HGs (mean age, 45 years) have participated in this survey. Among HBsAg-positive patients, Delta infection was sought in only 89% of cases. Liver fibrosis was assessed using FibroScan in 77% of the cases and by liver biopsy in 81% of the cases. A treatment was proposed for patients with >F2 liver fibrosis in 49% of the cases regardless of transaminase levels and for all the patients by 39% of HGs. Responding HGs proposed a treatment using pegylated interferon in 50% of cases, bulevirtide in 45% of cases and a combination of pegylated interferon and bulevirtide in 40.5% of cases. Among the criteria to evaluate the treatment efficacy, a decrease or a normalization of transaminases was retained by 89% of responding HGs, a reduction of liver fibrosis score for 70% of them, an undetectable delta RNA and HBsAg for 55% of them and a 2 log 10 decline in delta viremia for 62% of the cases. CONCLUSION: Hepatitis Delta screening was not systematically performed in HBsAg-positive patients despite the probable awareness and knowledge of the few responders who were able to prescribe treatments of hepatitis delta.

Optimization of Ganciclovir and Valganciclovir Starting Dose in Children by Machine Learning.

BACKGROUND AND OBJECTIVES: Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target. MATERIALS AND METHODS: The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC0-24 within 40-60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively). RESULTS: A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both). CONCLUSION: The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively.