Drug Regimens Research Articles

Targeted delivery of antitubercular drugs using glucan lipid particles.

Tuberculosis (TB) causes an estimated 10.8 million cases each year and remains one of the leading causes of infectious death. Effective treatment is complicated due to the lengthy drug regimen required to prevent relapse and treatment failure. A primary challenge is delivering drugs effectively to lung granulomas, where TB bacteria can persist. Here, we developed yeast-derived glucan lipid microparticles (GLPs) as a novel delivery system to efficiently encapsulate and deliver TB drugs directly to lung tissue via intranasal administration. Of the formulations evaluated, GLP-encapsulated clofazimine achieved increased lung drug levels and reduced bacterial burden in TB-infected mice. The use of GLPs offers a promising approach to improve TB treatment by enabling targeted drug delivery to infection sites within the lungs.

Selection and prioritization of candidate combination regimens for the treatment of tuberculosis

Accelerated tuberculosis drug discovery has increased the number of plausible multidrug regimens. Testing every drug combination in vivo is impractical, and varied experimental conditions make it challenging to compare results between experiments. Using published treatment efficacy data from a mouse tuberculosis model treated with candidate combination regimens, we trained and externally validated integrative mathematical models to predict relapse in mice and to rank both previously experimentally studied and unstudied regimens by their sterilization potential. We generated 18 datasets of 18 candidate regimens (comprising 11 drugs of six classes, including fluoroquinolone, nitroimidazole, diarylquinolines, and oxazolidinones), with 2965 relapse and 1544 colony-forming unit (CFU) observations for analysis. Statistical and machine learning techniques were applied to predict the probability of relapse in mice. The locked down mathematical model had an area under the receiver operating characteristic curve (AUROC) of 0.910 and showed that bacterial kill measured by longitudinal CFU cannot account for relapse alone and that sterilization is drug dependent. The diarylquinolines had the highest predicted sterilizing activity in the mouse model, and the addition of pyrazinamide to drug regimens provided the shortest estimated tuberculosis treatment duration to cure in mice. The mathematical model predicted the effect of treatment combinations, and these predictions were validated by conducting 11 experiments on previously unstudied regimens, achieving an AUROC of 0.829. We surmise that the next generation of tuberculosis drugs are highly effective at treatment shortening and suggest that there are several promising three- and four-drug regimens that should be advanced to clinical trials.

Efficacy of carbonyl cyanide-3-chlorophenylhydrazone in combination with antibiotics against Mycobacterium abscessus.

Given the intrinsic resistance of Mycobacterium abscessus to a wide range of conventional antibiotics, it is urgent to explore new therapeutic approaches to manage this infection effectively. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a proton pump inhibitor, has shown good bacteriostatic activity against M. abscessus. This study aimed to determine its synergistic antimicrobial effects when combined with commonly used antibiotics. The M. abscessus reference strain and 39 clinical isolates were collected. The minimum inhibitory concentration and fractional inhibitory concentration index were determined for the combined treatment using CCCP with various antibiotics including clarithromycin, amikacin, linezolid, bedaquiline, and clofazimine. A time-killing assay was used to measure the effect of the combined drug regimens quantitatively. The simultaneous use of CCCP with traditional antibiotics shows a synergistic effect across a wide range, significantly boosting the ability to inhibit the growth of M. abscessus throughout its growth phases. When CCCP is used in combination with clarithromycin, amikacin, and linezolid, it produces a synergistic effect on both the standard strain and most clinical isolates. When CCCP is paired with bedaquiline and clofazimine, it exhibits additive effects. Moreover, high levels of CCCP in combination with other antibiotics were found to rapidly eradicate the bacteria. The use of CCCP as a potential treatment for M. abscessus infections shows promising results, especially when combined with other antibiotics to achieve a potent bactericidal effect.IMPORTANCEMycobacterium abscessus poses a significant public health threat due to its intrinsic resistance to a broad spectrum of conventional antibiotics. This resistance necessitates urgently exploring novel therapeutic strategies to effectively combat infections caused by this pathogen. Our previous research has identified carbonyl cyanide-3-chlorophenylhydrazone (CCCP) as a potent direct antimicrobial agent against M. abscessus and as an enhancer of clarithromycin activity. Our results demonstrate that the concurrent administration of CCCP with traditional antibiotics exhibits a synergistic effect across a wide range, which could be crucial for overcoming the challenges posed by M. abscessus infections. Furthermore, the use of high concentrations of CCCP in combination with other antibiotics was found to rapidly eliminate M. abscessus, suggesting a potential therapeutic advantage. These insights not only advance our understanding of antimicrobial synergy but also hold promise for the development of more effective treatment regimens against drug-resistant M. abscessus infections.

Descriptive analysis of the efficacity of R-GEMOX /R-IE/R-CEPP in patients with relapsed/refractory (R/R) transplant-ineligible diffuse large B-cell lymphoma (DLBCL).

Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) ineligible for Hematopoietic Stem Cell Transplantation (HSCT) may benefit from a second line anticancer drug regimen but real-life outcomes are lacking. To describe the efficacity of 3 anticancer drug regimens (Gemcitabine and Oxaliplatin GEMOX; Ifosfamide and Etoposide IE; Cyclophosphamide, Etoposide, Procarbazine and Prednisone CEPP) combined with Rituximab (R-) in terms of progression-free (PFS) and overall survival (OS). Retrospective study including R/R DLBCL patients HSCT ineligible who received at least one cycle of R-GEMOX, R-IE or R-CEPP between 2010 and 2022. Demographic, clinical, biological and survival data were collected. Univariate and multivariate analysis were performed to identify associated variables with survival outcomes. Sixty-two patients (median age 78 [40-102] with predominantly stage III-IV DLBCL (n = 49, 79%), non-germinal center-B like (n = 27, 44%) were included. Median OS and PFS were 9 (CI95% [3-10]) and 4 months (CI95% [2-13]) for R-GEMOX, 4 (CI95% [2-6]) and 1 month (CI95% [1-4]) for R-IE and 5 (CI95% [3-6]) and 3 months (CI95% [2-15]) for R-CEPP, respectively. Univariate analysis selects ECOG, aa-IPI scores, LDH rate and Ann-Arbor stage with no independently association in multivariate analysis. All three regimens show modest survival benefit especially between last anticancer treatment course and death. Emergence of bispecific antibodies and Cart-cells for which real-life benefits have yet to be demonstrated could be coupled with improved access to early palliative care.

A Study Of the effect of Sex on drug dosing, concentrations, and pharmacogenomics in the Montreal Heart Institute Hospital Cohort (SOS-PGx): methodology and research progress.

Women are underrepresented in drug development trials and there is no sex-tailored drug regimen for most medications. It has been repeatedly shown that women have more adverse drug reactions than men for several medications. These differences could be explained by higher dose-adjusted drug concentrations in women. Thus, we aim to identify sex-related differences and to characterize the clinical and genetic predictors of these differences in drug concentrations, dosing, and adherence for 47 commonly used drugs in a large cohort. The objective of this article is to present an overview of the methods and characteristics of the study population. We performed a cross-sectional study that included 10,082 men and women of European ancestry aged ≥ 18years from the Montreal Heart Institute Hospital Cohort taking at least one of the 47 medications regularly. Of the 10,082 participants included, 36% were women. Women had lower weight, height, waist girth, and body mass index than men, but they had higher hip girth (all p < 0.001). Men had a higher level of education and annual income and were more likely to be employed full-time compared to women. Furthermore, men had a higher prevalence of hypertension, type2 diabetes, dyslipidemia, andmyocardial infarction (all p < 0.001) and were more likely receiving lipid-lowering agents, beta-blockers, antidiabetic drugs, and angiotensin-converting enzyme inhibitors. Conversely, proton pump inhibitors were more prevalent in women. Interestingly, nearly half of the women had a history of drug allergy or intolerance, compared with less than one-third of the men (p < 0.001). This study has a high potential in understanding eventual sex differences in drug dosing requirements and will most likely provide useful information to personalize drug regimens in women.

CRISPR-Cas12a-based detection and differentiation of Mycobacterium spp.

Mycobacterium species cause several vital human diseases, including tuberculosis and non-tuberculous mycobacterial infections which are treated with different drug regimens Therefore, accurate and rapid diagnosis is essential for effective treatment and controlling the spread of these pathogens. This study aims to develop the isothermal method combining RPA and CRISPR-Cas12a techniques, named as MyTRACK, to detect and differentiate major clinical mycobacteria at the species level. The assay has no cross-reactivity with limit of detection of 1 to 100 copies/reaction for various targeted mycobacteria. The results demonstrated 100 % specificity and 92.59 % to 100 % sensitivity in clinical isolates and were consistent with the culture technique with LPA for clinical samples. The MyTRACK assay is an effective, portable, rapid, and accurate screening method for mycobacterial detection and identification, especially in low-resource clinical settings.

24-week, all-oral regimens for pulmonary rifampicin-resistant tuberculosis in TB-PRACTECAL trial sites: an economic evaluation.

New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial. This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings. BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care. This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system. Médecins Sans Frontières.

The Analgesic Effect of a Transdermal Lappaconitine Patch Combined With Ibuprofen Suspension for Children After Adenoidectomy and Tonsillectomy: A Randomized Clinical Trial

To study the analgesic effects and side effects of a transdermal lappaconitine (TLA) patch, ibuprofen suspension (IS), and TLA combined with IS (TLACIS) after adenoidectomy and tonsillectomy. Prospective, randomized clinical trial. The patients were randomized into three groups defined by different analgesic drug regimens: the TLA group, the IS group, and the TLACIS group. Pain scores at 2, 12, and 24hours after surgery and adverse-event reports within the first postoperative week were collected. Ultimately, this study included 102 cases in the TLA group, 101 cases in the IS group, and 101 cases in the TLACIS group. At 2hours after surgery, the pain scores of the TLA and the TLACIS groups were both significantly lower than that of the IS group (all P<.05). At 12 and 24hours after surgery, the pain score of the TLACIS group was significantly lower than those of the TLA and IS groups (all P<.05); furthermore, the pain score of the IS group was significantly lower than that of the TLA group (P<.05). Within 1week after the operation, there was no significant difference in the incidence of adverse events. The addition of a TLA patch can speed the onset of analgesia. In terms of analgesic effects, IS alone is more advantageous than TLA alone, while the combination of TLA and IS has the best analgesic effect. No significant differences were found in the incidence of adverse events among the three regimens.

Experimental hypothermia by cold air: a randomized, double-blind, placebo-controlled crossover trial

BackgroundAccidental hypothermia is associated with high morbidity and mortality. Research on treatment strategies for accidental hypothermia is complicated by the low incidence and heterogeneous patient population. We have developed a new method for clinical trials of experimental hypothermia, to enable further studies of active rewarming. If cold ambient air is effective as a cooling method, this would mimic the most frequent clinical setting of hypothermic patients and provide a feasible cooling method for field studies. We aimed to induce mild hypothermia in healthy volunteers by exposure to cold ambient air, and tested the hypothesis that drug-induced suppression of endogenous thermoregulation would be required.MethodsIn a randomized, double-blind, crossover design, 15 healthy volunteers wearing wet clothes were put in a windy climate chamber set to 5 °C. Each participant completed the experimental procedure twice, once receiving active drugs (meperidine and buspirone) and once receiving placebo. The experiments were separated by a one-week wash-out period. Primary outcome was core temperature at termination, defined as 3 h of exposure or 35 °C. The between-groups difference was assessed using analysis of covariance (ANCOVA) with left censoring (Tobit model) and individual random intercept. Secondary outcomes were trajectory of core temperature and reduction of shivering.ResultsAt termination, the active drug vs placebo group differed in temperature by 1.4 °C. With adjustment for the removal of participants reaching 35 °C, the estimated mean difference was 1.7 °C (1.4–2.0, p < 0.001). Shivering was effectively reduced, but not completely inhibited by the drug regimen, and core temperature declined at a rate of − 0.82 °C per hour.ConclusionThe novel protocol utilizing cold air as a cooling method and drug-induced suppression of endogenous thermoregulation, is effective and enables future research projects. We have provided suggestions for minor alterations.Trial registration:EudraCT ID 2023–506020-81–00.

Incidence and predictors of seizure-related injuries among epileptic patients undergoing follow-up treatment at public hospitals in Central Ethiopia

Seizure-related injuries represent a significant concern for both individuals with epilepsy and their caregivers. Compared to the general population, those diagnosed with epilepsy face a heightened risk of sustaining injuries. Despite this, there is a notable scarcity of data regarding seizure-related injuries among epileptic patients. This study aimed to evaluate the incidence of seizure-related injuries and identify their predictors among epileptic patients undergoing follow-up treatment at selected public hospitals in Central Ethiopia, in 2023. A prospective follow-up study was carried out in selected public hospitals in central Ethiopia. The study included epileptic patients aged ≥ 18 years who had not experienced any previous injury during follow-up treatment from January 1st, 2023, to December 31st, 2023. Data collection involved conducting interviews with participants using a structured questionnaire and reviewing patients’ charts. Univariate analysis, multivariate, and regression analysis were performed to identify potential associations between variables and seizure-related injuries. Variables were deemed significantly associated with seizure-related injuries if they attained a p value of 0.05 with a 95% confidence interval. Out of the 561 participants, 265 (47.2%) experienced seizure-related injuries (95% CI 43.12, 51.38). The incidence density rate of seizure-related injuries among epileptic patients was 11.97 per 100 person-months of observation (95% CI 10.61, 13.50). In multivariate analysis, epileptic patients who had generalized tonic–clonic seizures (adjusted hazard ratio 1.4, 95% CI 1.07–1.84), comorbidities (adjusted hazard ratio 1.3, 95% CI 1.11–1.71), were on polytherapy drug regimens (adjusted hazard ratio 1.80, 95% CI 0.30–2.49), and consumed alcoholic drinks (adjusted hazard ratio 1.5, 95% CI 1.21–1.89) were identified as independent predictors of seizure-related injuries. The incidence rate of seizure-related injuries among epileptic patients was found to be significant. Risk factors identified included experiencing generalized tonic–clonic seizures, having at least one additional health condition, being on multiple medications, and consuming alcohol. To improve survival from injuries, targeted precautions for generalized tonic–clonic seizures, strict adherence to prescribed medication regimens, and avoiding alcohol consumption are recommended.

P-574. Extrapolating Expected Efficacy, Safety, and Pharmacokinetics (PK) of Dolutegravir/Lamivudine (DTG/3TC) in Pregnant People Living with HIV-1 from Pregnancy Data with Combination DTG and/or 3TC Antiretroviral Therapies

Abstract Background Minimizing fetal exposure to unnecessary drugs is a guiding principle during pregnancy. DTG/3TC has demonstrated efficacy, a high barrier to resistance, and a favorable safety profile. Data on DTG/3TC use in pregnant people living with HIV-1 are limited; however, safety and PK data for the individual components are extensive from DTG- and 3TC-containing 3-drug regimens (3DRs) as preferred regimens in pregnancy. Randomized trial data and PK from pregnant participants receiving DTG 3DRs or 2-drug regimens were used to extrapolate anticipated DTG/3TC efficacy, safety, and PK in pregnancy. Methods A literature review of articles, conferences, Antiretroviral Pregnancy Registry (APR) Interim Summary, and other non-interventional studies including DTG and/or 3TC in PubMed (Jan 1998-Nov 2023) using the search terms dolutegravir, lamivudine, and pregnancy was conducted. Efficacy, safety, PK, vertical transmission, and birth outcomes data were extracted. Clinical utility of DTG/3TC in pregnancy was evaluated in context of current perinatal treatment guidelines. Results Two studies evaluated DTG/3TC efficacy and safety in pregnancy: 30/31 (97%) participants maintained virologic suppression (&amp;lt; 50 c/mL); no vertical transmission occurred. Among 194 studies of DTG and 492 of 3TC, 3 randomized trials of DTG 3DR efficacy and safety in pregnancy were found. While DTG PK in pregnancy was generally lower and 3TC PK was slightly lower than postpartum, both were well above thresholds associated with efficacy in non-pregnant adults. Overall birth defect prevalence rate with DTG exposure at conception was 0.95% (16/1683, Tsepamo) and 0.88% (43/4902, Eswatini). The APR reported overall birth defect prevalence of 3.3% (32/957) with first-trimester and 5.3% (29/549) with second/third-trimester DTG exposure, which did not significantly differ from the population-expected rate (Metropolitan Atlanta Congenital Defects Program, 2.7%; Texas Birth Defects Registry, 4.2%). Conclusion DTG/3TC is anticipated to be similarly effective and tolerated for parental health and vertical transmission prevention with fetal exposure to fewer drugs. Pregnancy is not anticipated to significantly impact DTG/3TC exposure. DTG and 3TC are well tolerated with a well-established safety profile in pregnancy. Disclosures William R. Short, MD, Gilead: Grant/Research Support|Janssen: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Parul Patel, MSW, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Gustavo Verdier, BSc, BPharm, MBA, ViiV Healthcare: Employee Ana Puga, MD, FAAP, AAHIVS, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Andrew Weber, MS, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Leigh Ragone, MS, GlaxoSmithKline: Stocks/Bonds (Public Company)|ViiV Healthcare: Full time employee Eva Fernvik, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Vani Vannappagari, MBBS, MPH, PhD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Full time Employee|ViiV Healthcare: Stocks/Bonds (Public Company) V. Paul DiMondi, PharmD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Clifford B. Jones, BSc MSc MB ChB, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee

P-576. Real-world Experience with the Two-Drug Regimen Dolutegravir/Lamivudine for the Treatment of HIV-1 among Vulnerable People Living with HIV in Canada: Preliminary Results from a Chart Review Study

Abstract Background Compared to the general population of people living with HIV, vulnerable people, such as those who use drugs, are disproportionately affected by HIV, and are predisposed to lower adherence to antiretroviral therapies (ARTs), which may result in poorer virologic suppression, worse health outcomes, and higher HIV transmission rates. Some may benefit from simpler single-tablet regimens that are effective, well tolerated, and limit exposure to unnecessary medications. We evaluated clinical outcomes in vulnerable people living with HIV who switched to the single-tablet, 2-drug regimen dolutegravir/lamivudine (DTG/3TC). Methods This ongoing chart review study included people living with HIV (≥ 18 years) in Canada who switched to DTG/3TC between 09/09/2019 and 31/05/2023, and had ≥ 1 of the following vulnerability criteria: recent drug use, opioid agonist use, recent or well-documented history of unstable housing or receiving social assistance, Indigenous identity, or ≥ 65 years of age with diminished autonomy (‘vulnerable senior’). Descriptive summary statistics were generated for demographic and clinical characteristics at baseline (≤ 12 months pre-switch), and viral load and CD4+ cell counts at 6 (± 2) and 12 (± 2) months post-switch. Interim results are reported for the ongoing study. Results Across 5 sites, 20 eligible people were included (mean age: 49.9 ± 13.0 years; male: 80%; drug use: 80%; vulnerable senior: 20%). Simplification of ART was the predominant reason for switch to DTG/3TC (n=11, 55%). At the time of analysis, 80% (n=16) had at least 6 months of follow-up, and one discontinued DTG/3TC due to intolerance. At 6 months, of those with test results, 8/8 were virally suppressed (&amp;lt; 50 c/mL), and median (IQR) CD4+ cell count was 815 (122.5) cells/mm3. At 12 months, 11/12 were virally suppressed (&amp;lt; 50 c/mL), and median CD4+ cell count was 920 (180) cells/mm3 (n=10). Conclusion Preliminary results suggest promising effectiveness outcomes among vulnerable people living with HIV who switch to DTG/3TC. These results support the continued expansion of this study to include more people. Disclosures Emmanuelle Huchet, MD, AbbVie: Honoraria|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Indivior: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Joann K. Ban, PharmD, MSc, GSK: employee Adenike R. Adelakun, BPharm, MSc, GSK: employee Katherine Osenenko, MCPM, Broadstreet HEOR: employee|ViiV Healthcare: Funding for the conduct of this work Isabelle Hardy, PhD, ViiV Healthcare: employee Elaine Stewart, HBSc, ViiV Healthcare: employee Michael McKimm, BSc, ViiV Healthcare: employee Jean-Francois Fortin, MD, ViiV Healthcare: employee Madeleine Crabtree, MPH, Broadstreet HEOR: employee|ViiV Healthcare: Funding for the conduct of this work Karissa Johnston, MSc, PhD, Broadstreet HEOR: employee|ViiV Healthcare: Funding for the conduct of this work Brian Conway, MD, AbbVie: Advisor/Consultant|AbbVie: Grant/Research Support|AbbVie: Honoraria|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|AstraZeneca: Honoraria|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|GSK: Advisor/Consultant|GSK: Grant/Research Support|GSK: Honoraria|Indivior Canada: Advisor/Consultant|Indivior Canada: Grant/Research Support|Indivior Canada: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Honoraria|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Honoraria|Seqirus: Advisor/Consultant|Seqirus: Grant/Research Support|Seqirus: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria V. Paul DiMondi, PharmD, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee

P-539. Does Switching from Triple (or Quadruple)-Drug Regimen to Double-Drug Regimen with Oral INSTIs Reduce Drug-Related Adverse Events (DRAEs) and Toxicity in Virologically Suppressed People with HIV? SATISFACTION Study

Abstract Background Triple or quadruple drug regimens (3 or 4DR) remain the gold standard for HIV treatment. However, there is currently a trend towards therapy simplification from 3 or 4DR to double-drug regimens (2DR) based on Integrase Strand Transfer Inhibitors (INSTIs). Switching to 2DR is not based on increased efficacy, as studies suggest non-inferiority of 2DR, but aims to reduce adverse events and long-term toxicity associated with prolonged exposure to current antiretroviral drugs. However, to date, neither clinical trials nor real-world data have confirmed this hypothesis. This study aims to describe the proportion of DRAEs reported in phase III and IV studies in virologically suppressed people with HIV (PWH) on 3 or 4DR and those who have switched from 3 or 4DR to 2DR with oral INSTIs at ≥ 48 weeks. Percentage of DRAEs and DRAEs leading to discontinuation Percentage of DRAEs and DRAEs leading to discontinuation Methods A systematic literature review was conducted searching on the main databases (PubMed, ClinicalTrials.gov, EU Clinical Trials Register, Cochrane and Embase) from March 2014 to March 2024, as well as on the main conferences from March 2022 to March 2024. We included phase III and phase IV studies evaluating the switch from 3 or 4DR to 2DR based on oral second-generation INSTIs in virologically suppressed PWH, with ≥ 48 weeks of follow-up. A meta-analysis is being conducted in studies with 48-week follow-up. Financial support: Gilead Sciences Results Nine publications met the inclusion criteria. Eight publications corresponded to three phase III clinical trials (TANGO, SALSA and SWORD) at different follow-up periods and one to a phase IV study (DOLAM), with a 48-week follow-up. The percentage of DRAEs and DRAEs leading to discontinuation increased in patients who switched to 2DR ([6-20%] and [2-4%], respectively) compared to those who remained in 3 or 4DR ([0-6%] and [0-1%]) at 48 weeks in all studies (Figure 1). A similar trend was observed with longer follow-up times. Differences observed in laboratory parameters when switching from 3 or 4DR to 2DR were not clinically relevant. Conclusion Therapy simplification from 3 or 4DR to 2DR with oral second-generation INSTIs in virologically suppressed PWH at ≥ 48 week did not enhance the safety and tolerability profile compared with 3 or 4DR continuation, according to data reported in phase III clinical trials and phase IV studies. Disclosures Antonio Antela, MD, PhD, Gilead: Honoraria|Janssen: Advisor/Consultant|MSD: Honoraria|ViiV: Board Member Pere Domingo-Pedrol, Medical Doctor, Gilead: Advisor/Consultant|Gilead: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Francisco Mariano Jover-Díaz, Medical Doctor, Gilead: Advisor/Consultant|Gilead: Honoraria|Janssen: Advisor/Consultant|ViiV: Advisor/Consultant Javier Martínez-Sanz, Medical Doctor, Gilead Science: Advisor/Consultant|Gilead Science: Grant/Research Support|Gilead Science: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|ViV: Honoraria

Peculiarities of morphological changes in the lamina cribrosa in patients with myopia and options of drug influence on its state

The literature review substantiates the need to study the morphological changes in the lamina cribrosa in patients with myopia. The authors discuss the pathogenesis of axial myopia, namely, changes in the lamina cribrosa in pathological elongation of the anteroposterior axis of the eye. It is interesting to review the methods for the treatment and diagnosis of myopia, which remain extremely difficult tasks due to the lack of knowledge about most pathogenetic mechanisms of its development. The authors mention the commonly available and well-known spectra of treatment measures: conservative, surgical, laser methods of treatment and diagnosis of myopia, as well as modern drug regimens to control the progression of myopic changes. To date, there are quite a few studies on changes in the lamina cribrosa in glaucoma. However, research on the parameters of lamina cribrosa changes in myopia is rare in scientific literature. A modern approach to the diagnosis of changes in the lamina cribrosa will help clarify the mechanisms of visual impairment in these patients and will serve as the basis for the development of methods for the prevention and treatment of blindness in people suffering from myopia.

Adult Anaesthesia Practice at Zinder National Hospital

Introduction: Anesthesia allows surgery to proceed smoothly, with pain suppression, patient immobility and neurovegetative protection. The aim of this study is to describe anesthetic practice in adults at Zinder National Hospital. Patients and Method: it was a prospective cross-sectional study including patients aged at least 16 undergoing surgery at the Zinder national hospital from December 4, 2023 to March 3, 2024 (3 months). Results: During the study period, 560 anaesthetic procedures were performed in the operating theatre, of which 329 (58.8%) involved patients aged 16 or over. The mean age was 38.7±17.8, with extremes of 16 and 85 years. Past history was present in 30% of patients, dominated by hypertension. The types of surgery were: visceral surgery 48.9% followed by traumatology 27.1%, all patients were evaluated before anesthesia. General anesthesia (GA) was used in 61.4% of cases. In 55.3% of cases, patients were classified as ASA I. The drug regimen most commonly used for GA was: fentanyl, suxamethonium and ketamine in 38.4% of cases, and for spinal anesthesia, the bupivacaine-fentanyl combination. Anesthesia was provided by 2 anesthesiologists and 10 anesthesia technicians. More than half the patients developed adverse events in the operating room, and one (1) patient died (0.3%). Conclusion: This study provides us with information on the socio-demographic characteristics of patients, the types of surgery and the characteristics of adult anaesthesia at Zinder National Hospital. A number of aspects remain to be improved, including the number of anaesthetists and the availability of equipment such as respirators and capnographs.

Programmable Porous Silicon Microparticles for Temporally Staged Drug Delivery in Combination Cancer Immunotherapy.

Combination therapies using checkpoint inhibitors with immunostimulatory agonists have attracted great attention due to their synergistic therapeutic effects for cancer treatment. However, such combination immunotherapies require specific timing of doses to show sufficient antitumor efficacy. Sequential treatment usually requires multiple administrations of the individual drugs at specific time points, thus increasing the complexity of the drug regimen and compromising patient compliance. Here, we introduce an injectable porous silicon microparticle (pSiMP) for combination cancer immunotherapy where its multilayered nanopore structure was electrochemically programmed to achieve release of three distinct immunomodulatory drugs in the right sequence at the desired time. We find the optimal sequential treatment timeline of stimulator of interferon genes (STING) agonist, anti-OX40 antibody (aOX40), and anti-PD-1 antibody (aPD-1) for immunosuppressive tumors. We show that a single intratumoral injection of a cocktail of release-programmed pSiMPs coloaded with each antibody and a STING agonist significantly suppresses the tumor growth compared to conventional treatment involving sequential bolus injections, or an injection of pSiMPs configured to release all drugs at the same time, with no delay. With the timely release of immunomodulatory drugs, the programmable pSiMPs offer an effective treatment strategy for combination immunotherapy.

P0961 Establishing a new cellular therapy for patients with Ulcerative Colitis

Abstract Background Inflammatory Bowel Diseases (IBD), which include Crohn’s Disease and Ulcerative Colitis (UC), show an accelerated incidence rate, affecting up to 1% in Western countries, and an increased burden in healthcare costs, reaching up to 5.6 billion euros per year. Although there are several treatment options, the remission rates are around 30-60%, with primary non-response and loss of response to be the main reasons for changing treatment plans. Thus, there is a need for new therapeutic strategies targeting these groups of non-responding patients. Towards this, we are developing a novel cellular therapy for UC, using autologous transplantation of intestinal epithelial organoids. Methods Here, colonic epithelial cells will be isolated, expanded under GMP conditions, and transplanted into ulcerated colonic regions of patients with UC, to promote and accelerate mucosal healing. This initial strategy targets patients with localized ulceration unresponsive to first- and second-lines of treatments. Results We have established a robust protocol for expanding intestinal epithelial organoids. These organoids contain all major cell type populations that orchestrate the intestinal epithelium. We have successfully transplanted both murine and human colonic organoids into NOG mice. After successful engraftment onto the damaged intestinal mucosa, they promote and accelerate mucosal healing. Currently, we are establishing scale-up culturing methodologies, in order to expand our cell cultures to a number of cells that would be enough to promote mucosal healing during transplantation in humans. Finally, we are refining the cell culture conditions to be GMP-approved, and thus, registering our final product as acceptable to be used during human clinical trials. Conclusion Our approach could offer a new therapeutic option for patients with UC that do not respond to current drug regimens and are in need for an effective treatment.

Bioinformatic analysis of the therapeutic potential of the secretome released by menstrual blood-derived stromal cells (menscs) as an adjuvant in the treatment of ovarian cancer

Abstract Introduction Treatment of ovarian cancer (OC) usually consists of a combination of surgery and chemotherapy, with carboplatin, often in combination with paclitaxel, being the most employed drug regimen. While effective, this approach has significant side effects and is associated with long-term chemoresistance, highlighting the need for alternative therapeutic strategies. This study aims to evaluate, through in silico methods, the therapeutic potential of the secretome from menstrual blood-derived stromal cells (MenSCs) as a potential adjuvant to conventional OC therapy. Methods MenSCs (n=5) were cultured in DMEM with 1% ITS for 48 hours. The resulting conditioned medium was ultrafiltered (3 kDa) to obtain the secretome (S-MenSCs), which was then analysed using transcriptomics and proteomics. Bioinformatics tools were employed to identify OC-associated genes using DisGeNET, drug target genes via DGIdb, and to predict protein and miRNA interactions with these drug target genes using FunRich and miRTargetLink2.0, respectively. NcDR was used to establish miRNAs related to drug resistance. Subsequently, the proteins and miRNAs from S-MenSCs were compared with those previously identified, and various interaction networks were constructed using Cytoscape. Results S-MenSCs contained approximately one third of the proteins and miRNAs that interact with the target genes of both chemotherapeutics. Of these, 14 miRNAs were identified as chemosensitizers for paclitaxel. Conclusion S-MenSCs hold promise as an adjuvant agent, potentially allowing for the reduction of chemotherapeutic doses, thus decreasing adverse effects and overcoming chemoresistance, as determined in silico.

Real-World Effectiveness and Tolerability of Dolutegravir and Lamivudine 2-Drug Regimen in People Living with HIV: Systematic Literature Review and Meta-Analysis.

Dolutegravir (DTG) + lamivudine (3TC) demonstrated high rates of virologic suppression (VS) and low rates of virologic failure (VF), discontinuation, and drug resistance in randomized trials. Real-world evidence can support treatment effectiveness, safety, and tolerability in clinical practice and aid in treatment decisions. A systematic literature review (SLR) was conducted to identify studies using DTG + 3TC (January 2013-March 2024). Studies were screened to include observational studies reporting 48- or 96-week on-treatment VS, VF, or discontinuation outcomes; proportions of individuals with each outcome at each time point were estimated using random- and common-effects models. Of 249 SLR-identified publications, 43 reported consistently defined outcomes of interest at comparable time points, representing 1480 individuals naive to antiretroviral therapy (ART) and 12,234 individuals with prior ART experience. At weeks48 and 96, respectively, estimated proportions (95%CIs; random-effects model) with on-treatment VS were high (naive to ART, 0.964 [0.945-0.979] and 0.902 [0.816-0.966]; prior ART, 0.966 [0.950-0.980] and 0.971 [0.946-0.990]), with low estimated proportions experiencing VF (naive to ART, 0.001 [0.000-0.013] and 0.001 [0.000-0.008]; prior ART, 0.009 [0.005-0.015] and 0.015 [0.007-0.024]) and discontinuations for any reason (naive to ART, 0.052 [0.019-0.097] and 0.130 [0.084-0.183]; prior ART, 0.067 [0.042-0.098] and 0.084 [0.047-0.130]). Across identified studies (> 44,000 unique individuals), those reporting resistance outcomes at VF/blip (regardless of emergence) detected integrase strand transfer inhibitor (INSTI) mutations in 0 of 2346 individuals naive to ART and 0.02% (4/20,060) of individuals with prior ART experience (S147G, R263K, G118R + E138K, T66A + G118R + E138K); additionally, N155H was reported in an individual using DTG + 3TC with unknown baseline ART status. Overall treatment outcomes in real-world settings confirm the efficacy, tolerability, and high barrier to resistance seen in phase3 trials across diverse populations, including those naive to ART or with prior ART experience.

New Treatment Regimens, New Drugs, and New Treatment Goals for Lupus Nephritis.

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus, affecting roughly 40% of all lupus patients. With the introduction of cyclophosphamide and mycophenolate mofetil, outcomes have dramatically improved. However, 10% of patients still progress towards end-stage kidney disease, which carries an elevated mortality rate. In recent years, several novel agents have been approved for use or have shown preliminary evidence of efficacy in lupus nephritis. These agents include belimumab, voclosporin, and obinutuzumab, among others. Efficacy has also been demonstrated in recent trials combining older drugs. However, determining which patients would benefit the most from novel agents or combined drug regimens and whether these drugs might serve as an alternative to current remission-induction drug regimens rather than as add-on therapies remain unresolved issues. In this review, we will explore the current evidence regarding the efficacy of novel agents.