Pharmacoeconomic evaluation of the tixagevimab and cilgavimab combination using for pre-exposure prophylaxis of COVID-19

Aim. To evaluate pharmacoeconomic feasibility using of the tixagevimab and cilgavimab combination for pre-exposure prophylaxis of COVID-19 in immunocompromised patients. Materials and methods. Cost-effectiveness of tixagevimab and cilgavimab in persons 12 years old who weigh 40 kg and have either a history of allergy that prevents their vaccination against COVID-19 or moderate or immunocompromised was assessed based on PROVENT phase III study results. The quantity of life years or quality-adjusted life years gained was calculated. Direct medical cost associated with prophylaxis of COVID-19, treatment of infected patients and those experiencing long COVID post infection were assessed. Results were compared with wiliness-to-pay threshold, measured as tripled gross domestic product per capita and equal to 2.69 mln RUB in 2022. Results. Pre-exposure prophylaxis of COVID-19 results in additional 0.0287 life years or 0.0247 quality-adjusted life years. The cost of additional life year gained is equal to 1.12 mln RUB, the cost of additional quality-adjusted life years is 1.30 mln RUB. Both costs of additional life year and cost of quality-adjusted life years appeared to be significantly less compared to wiliness-to-pay threshold. Conclusion. Pre-exposure prophylaxis of COVID-19 with combination of tixagevimab and cilgavimab is economically feasible and may be recommended for wide use in Russian healthcare system

Streamlining the screening cascade for active Hepatitis C in Russia: A cost-effectiveness analysis.

ObjectiveScreening for hepatitis C in Russia is a complex process that involves several visits and stepwise testing, limiting adherence and substantially reducing the yield in the identification of active infections. We aimed to evaluate the cost-effectiveness of different screening algorithms from a health system perspective.MethodsA decision analytic model was applied to a hypothetical adult population eligible to participate in a general screening program for hepatitis C in Russia. The standard pathway (I: Screen for anti-HCV antibodies followed by a nucleic acid test for HCV RNA on antibody positives) was compared to three alternatives (II: Screen for antibodies, a reflexed test for HCV antigen on antibody positives, and RNA on antigen negatives; III: Screen for antibodies, a reflexed test for HCV antigen on antibody positives; IV: Screen for antigen). Each strategy considered a cascade of events (referral, adherence, testing, diagnosis) that must occur for screening to be effective. The primary measure of effectiveness was the number of diagnosed active infections. Calculations followed a health system perspective with costs derived from 2017 reimbursement rates and a willingness-to-pay of 2,000RUB ($82) per diagnosed active infection. Model was tested with deterministic and probabilistic sensitivity analyses.ResultsNon-adherence to screening stages reduced the capture rate of active infections in Strategy I from 79.0$3,681) for I to 53,072RUB ($2,180), 53,004RUB ($2,177), and 59,633RUB ($2,450) for II, III, and IV, respectively. With a probability of 97$-56; CI: -$206 to -$84). Below a willingness-to-pay of 91,000RUB ($3,738), Strategy IV was not cost-effective. Sensitivity analyses confirmed the robustness of results.ConclusionsTesting strategies for hepatitis C with HCV antigen on HCV antibody positive cases offer a streamlining opportunity for population screening programs. Those shall increase the chances for detecting active infections and are cost-effective over current practice in Russia

Safety and Immunogenicity of the GamTBvac, the Recombinant Subunit Tuberculosis Vaccine Candidate: A Phase II, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study

GamTBvac is a candidate tuberculosis vaccine with two fusion proteins, containing Ag85a, ESAT6, CFP10, and a dextran-binding domain (DBD). Phase II of a double-blind, randomized, multicenter, placebo-controlled study in parallel groups in healthy adults to evaluate the safety and immunogenicity of GamTBvac in 180 previously-vaccinated with Bacillus Calmette–Guérin vaccine (BCG) healthy volunteers without Mycobacterium tuberculosis (MTB) infection was conducted. The dose (0.5 mL) of either the study drug or a placebo was administered subcutaneously twice with an 8-week interval. At eight timepoints from 14 to 150 days, whole blood and sera were assayed. Antigen-specific T-cell responses were measured by an in-house interferon-gamma release assay (IGRA-test), the QuantiFERON (QTF) test, and intracellular cytokine staining (ICS). For antibody response detection, the bead-based multiplex immunoassay (MIA) was applied. The vaccine confirmed an acceptable safety profile previously shown in a first-in-human clinical study. After stimulation with both fusions, the highest median level of INF-γ was detected on day 21. The GamTBvac vaccine induced antigen-specific interferon-gamma release, Th1 cytokine-expressing CD4+ T-cells, and IgG responses and results support further clinical testing of GamTBvac

Base-Calling Algorithm with Vocabulary (BCV) Method for Analyzing Population Sequencing Chromatograms

<div><p>Sanger sequencing is a common method of reading DNA sequences. It is less expensive than high-throughput methods, and it is appropriate for numerous applications including molecular diagnostics. However, sequencing mixtures of similar DNA of pathogens with this method is challenging. This is important because most clinical samples contain such mixtures, rather than pure single strains. The traditional solution is to sequence selected clones of PCR products, a complicated, time-consuming, and expensive procedure. Here, we propose the base-calling with vocabulary (BCV) method that computationally deciphers Sanger chromatograms obtained from mixed DNA samples. The inputs to the BCV algorithm are a chromatogram and a dictionary of sequences that are similar to those we expect to obtain. We apply the base-calling function on a test dataset of chromatograms without ambiguous positions, as well as one with 3–14% sequence degeneracy. Furthermore, we use BCV to assemble a consensus sequence for an HIV genome fragment in a sample containing a mixture of viral DNA variants and to determine the positions of the indels. Finally, we detect drug-resistant <em>Mycobacterium tuberculosis</em> strains carrying frameshift mutations mixed with wild-type bacteria in the <em>pncA</em> gene, and roughly characterize bacterial communities in clinical samples by direct 16S rRNA sequencing.</p> </div

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Background &amp; Aims: Direct-acting antiviral (DAA) regimens provide a cure in &gt;95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in &gt;-1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing &gt;-2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses

The comparison of BCV main sequence assembling results with sequences of cloned PCR products.

<p>Phylogenetic tree shows relationships between consensus sequences (black squares) assembled from direct reads of the HIV protease gene fragment with sequences of clones (black circles) for sample GEN014DR.01A. The consensus assembled from two opposite direct reads with trimmed degenerate parts is denoted as D.vqa01; the one that is assembled by the BCV indel detection script is FR.main. F.main is the dominating DNA type extracted from a direct read in the forward direction by the BCV indel detection script; R.main is the same read in the opposite direction. H61 is the blastn best hit to sequence D.vqa01 used for scaling quasispecies variation (black circles).Reads in forward and reverse directions have different fractions of non-degenerate positions: F: 56/503 = 11%; R –430/492 = 87%. B: a node in the tree corresponding to HIV subtype B branch. The phylogenetic tree is constructed by the Minimum Evolution method <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054835#pone.0054835-Rzhetsky1" target="_blank">[66]</a> for the Maximum Composite Likelihood <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054835#pone.0054835-Tamura1" target="_blank">[67]</a> distance matrix by the MEGA 5 software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054835#pone.0054835-Tamura2" target="_blank">[68]</a>.</p

The shifting patterns in direct sequencing chromatograms.

<p>A. Sequences of 2 mixed DNA types (1 and 2) and their alignment. B and C. Chromatogram sequences (results of base-calling) for both reading directions are named bc-fw and bc-rev. The final Indels are assigned relatively to the main subgroup that is comprised of the DNA type, which has the higher fraction in the mixture. Italic underlined font shows shifting patterns. Bold shows the sequence portions that precede indel positions in each reading direction. Italics show the sequence portions of 2 DNA types that are aligned with the given coordinate shift.</p