Relationship between adherence to bictegravir/emtricitabine/tenofovir alafenamide fumarate and clinical outcomes in people with HIV in Japan: a claims database analysis.

A lack of adherence to long-term antiretroviral therapy may impact viral suppression. The current study examined the relationship between medication adherence and clinical outcomes in people with human immunodeficiency virus infection (PWH) receiving bictegravir, emtricitabine, and tenofovir alafenamide fumarate (B/F/TAF). A retrospective cohort study using two Japanese claims databases was conducted. Adherence was measured by the proportion of days covered (PDC). Patients were grouped into 3 PDC category and persistence was estimated by Kaplan-Meier method. Cox regression analysis was performed to investigate whether the PDC was associated with treatment discontinuation. Among 952 patients, 820 (86.1%), 95 (10.0%), and 37 (3.9%) patients were grouped into the PDC ≥ 90%, 80- < 90%, and < 80% groups, respectively. Across all PDC groups, more than 90% of patients who received B/F/TAF were receiving treatment at 1 year. There was no significant difference in the risk of discontinuation between the lower PDC groups (80- < 90% and < 80%) and the PDC ≥ 90% group (0.400 [0.096, 1.661]; 2.244 [0.663, 7.594], hazard ratio [95% confidence interval], respectively). A drug resistance test was implemented for 15 patients, none of whom discontinued B/F/TAF after the test. The results suggest that events that could cause discontinuation, such as virologic failure, were not associated with PDC.

Prevalence and clinical characteristics of people with HIV with limited treatment options in Japan: A Japanese claims data analysis.

INTRODUCTION: Long-term medication leads some people with HIV (PWH) to limited treatment options (LTO) due to multiple factors. The present study investigated the prevalence of PWH with LTO in Japan and their clinical characteristics, persistence, and adherence. METHODS: PWH who received antiretroviral therapy (ART) between 2017 and 2022 were identified in the Medical Data Vision (MDV) Japanese claims database. PWH with LTO were defined as: 1) receiving regimens indicative for LTO or 2) having a complex treatment history (≥4 different core agents, ≥11 ART agents). Prevalence by calendar year, clinical characteristics, persistence, and adherence measured by the proportion of days covered (PDC) of ART were investigated. RESULTS: A total of 5740 PWH were included, and 207 (3.6 %) were identified as LTO. Mean (SD) age was 50.3 (11.8) years, 148 (71.5 %) had evidence of AIDS-defining condition, and 25 (12.1 %) had hemophilia. The prevalence of PWH with LTO increased from 2.58 % in 2017 to 3.55 % in 2022. Persistence at 1 year was estimated as 70.3 % and mean PDC through 1 year was 96.7 %. CONCLUSION: Between the years 2017-2022, 3.6 % (approximately 200) Japanese PWH were identified as having LTO. The results of this analysis found clinical characteristics of PWH with LTO as older age and higher percentages with an AIDS-defining condition and hemophilia than the general HIV population. Low persistence indicates that treatment optimization is required in this population. These results will help health care providers to understand the clinical characteristics of PWH with LTO and may contribute to the establishment of appropriate treatment strategies.

The safety and effectiveness of remdesivir in a postmarketing surveillance study in Japan.

BACKGROUND: To evaluate the occurrence of adverse drug reactions (ADRs) and to assess mortality and health status in participants receiving remdesivir in real-world settings in Japan. METHODS: This postmarketing surveillance study used an all-case surveillance method for enrollment. Participants with SARS-CoV-2 infection administered remdesivir from July 2020 to November 2021 in Japan were eligible for inclusion. The observation period was from remdesivir treatment initiation to 4 weeks after the end of treatment or treatment discontinuation. Clinical status and outcomes were analyzed by Kaplan-Meier plots and compared across subgroups at baseline, Day 14, Day 28, and the final observation point. RESULTS: The analysis included 2128 participants (mean age, 67 years; 71.4 % male; 84.1 % with current comorbidities). ADRs and serious adverse drug reactions (SADRs) were reported among 10.4 % and 1.2 % participants, respectively. Overall, 191/2127 participants died (mortality rate [95 % confidence interval], 11.10 [9.66-12.75] per 100 person-months), 1511/2127 showed clinical improvement (117.8 [112.0-123.9] per 100 person-months), 1392/2127 recovered (103.9 [98.6-110.0] per 100 person-months), and 216/324 were extubated (107.0 [93.6-122.3] per 100 person-months). CONCLUSIONS: The incidence of ADRs and SADRs was low, and no new safety concerns were identified. Observed mortality and clinical improvement results were consistent with prior studies, confirming remdesivir's benefits in real-world settings in Japan.

Synthesis and antibacterial activity of 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides.

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide derivatives with activities against resistant pathogens is urgently needed. A series of novel 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides has been synthesized from erythromycin A. These compounds have shown very promising in vitro and in vivo antibacterial activities against key respiratory pathogens including erythromycin-susceptible/resistant strains.

Synthesis and structure-activity relationship of a novel class of 15-membered macrolide antibiotics known as '11a-azalides'.

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.

Synthesis and antibacterial activity of a novel class of 15-membered macrolide antibiotics, "11a-azalides".

An efficient method for the reconstruction of the 9-dihydroerythromycin A macrolactone skeleton has been established. The key steps are oxidative cleavage at the 11,12-position and reconstruction after insertion of an appropriate functionalized amino alcohol. Novel 15-membered macrolides, we named as "11a-azalides", were synthesized based on the above methodology and evaluated for their antibacterial activity. Among them, (13R)-benzyloxymethyl-11a-azalide showed the most potent Streptococcus pneumoniae activity, with improved activity against a representative erythromycin-resistant strain compared to clarithromycin (CAM).

Using biological performance similarity to inform disaccharide library design.

Designing better small-molecule discovery libraries requires having methods to assess the consequences of different synthesis decisions on the biological performance of resulting library members. Since we are particularly interested in how stereochemistry affects performance in biological assays, we prepared a disaccharide library containing systematic stereochemical variations, assayed the library for different biological effects, and developed methods to assess the similarity of performance between members across multiple assays. These methods allow us to ask which subsets of stereochemical features best predict similarity in patterns of biological performance between individual members and which features produce the greatest variation of outcomes. We anticipate that the data-analysis approach presented here can be generalized to other sets of biological assays and other chemical descriptors. Methods to assess which structural features of library members produce the greatest similarity in performance for a given set of biological assays should help prioritize synthesis decisions in second-generation library development targeting the underlying cell-biological processes. Methods to assess which structural features of library members produce the greatest variation in performance should help guide decisions about what synthetic methods need to be developed to make optimal small-molecule screening collections.

Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl)acetylerythromycin A derivatives.

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.