Subsequent Treatment Failure Research Articles

Intestinal ultrasound accurately predicts future therapy failure in Crohn's disease patients in a biologics-induced remission.

Intestinal ultrasound (IUS) is used to assess disease activity, complications, and treatment follow-up in Crohn's disease (CD). Less is known about the association of disease activity on IUS with the risk of future disease relapse during biologically sustained clinical remission in CD. The study aimed to investigate the association between IUS activity parameters and subsequent therapy failure in asymptomatic biologically treated patients with CD. A retrospective cohort study examined the association between IUS parameters and forthcoming therapy failure (drug discontinuation, dose escalation, corticosteroid use, hospitalization, or surgery) in CD patients on biological therapy in remission. A total of 57 patients with ileal (65%) or ileocolonic (35%) CD on biological therapy were included in the study. Therapy failure occurred in 50.8% [defined as need for dose escalation (31%), drug discontinuation (51.7%), steroid use (10.5%), and hospitalization (6.8%)] during a median follow-up of 5 (SD + 9.5) months after IUS. On univariate analysis, a bowel wall thickness (BWT) of 2.5 vs. 4 mm (P = 0.005), the existence of an enlarged lymph node (P = 0.02), and the loss of bowel wall stratification (P = 0.01) were correlated with therapy failure. On multivariable analysis, only BWT ≥ 4 mm was associated with the risk of future treatment failure (hazard ratio, 3.7; 95% confidence interval, 0.6-15; P = 0.02). Our findings suggest that BWT ≥4 mm during clinical remission is associated with subsequent treatment failure in patients with CD treated with biologics. Our results support the use of IUS for monitoring CD during remission and may point to a novel threshold for predicting disease reactivation.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Phenotypic and genotypic identification of class C and D β-lactamases in clinical isolates of Pseudomonas aeruginosa: a cross-sectional study.

The emergence of Pseudomonas aeruginosa (P. aeruginosa) antibiotic resistance is an important public health problem worldwide that can negatively affect infection control. Therefore, obtaining knowledge about antibiotic resistance mechanisms is necessary for infection control policies. This study aimed to determine the frequency of class C and D β-lactamases in P. aeruginosa strains isolated from patients referred to Ardabil hospitals using phenotypic and genotypic tests. Phenotypic detection of β-lactamases including AmpC cephalosporinase, oxacillinase (OXA)-type extended-spectrum β-lactamases (ESBLs), and OXA-type carbapenemases were performed using the disk diffusion-based methods. Amplification of genes encoding classes C (ampC and FOX genes) and D (OXA-1, OXA-2, OXA-10, OXA-23, and OXA-48 genes) β-lactamases was performed using the polymerase chain reaction (PCR) method. A quantitative reverse transcription PCR (qRT-PCR) method was used to determine the expression level of the ampC gene among multiple drug-resistant and imipenem-resistant P. aeruginosa strains. In phenotypic tests, the prevalence of AmpC cephalosporinase, OXA-type ESBLs, and OXA-type carbapenemases were 52.5%, 7.2%, and 95.8%, respectively. In genotypic tests, the prevalence of ampC, FOX, OXA-1, OXA-2, OXA-10, OXA-23, and OXA-48 genes were 100%, 0%, 4.3%, 60.8%, 42%, 29.7%, and 2.9%, respectively. In addition, the ampC gene overexpression was seen in 16 (33.3%) drug-resistant P. aeruginosa clinical isolates. Given the presence of class C and D β-lactamases in clinical isolates of P. aeruginosa in Ardabil hospitals, early detection of these strains can help prevent the spread of resistant strains in hospital environments and subsequent treatment failure.

Role of volume and inoculum in MIC assessment: a study with meropenem and Klebsiella pneumoniae.

Pharmacodynamic parameters evaluated under conditions that simulate an infection site volume and microbial load might reveal hidden risks of resistance selection and subsequent treatment failure. The study aimed to investigate the predictive potential of MICs determined at various conditions on the antimicrobial effect and emergence of resistance. We assessed meropenem MICs (microdilution: 0.2 mL, 5 × 105 cfu/mL; macrodilution: 2 mL, 5 × 105 cfu/mL), MICHVs (220 mL, 5 × 105 cfu/mL), MICHIs (0.2 mL, 5 × 107 cfu/mL) and MICHVIs (220 mL, 5 × 107 cfu/mL) for five Klebsiella pneumoniae strains and analysed these values alongside the results of experiments in a dynamic in vitro model. A clinically relevant meropenem dosing regimen was simulated and the starting bacterial inocula were 106 and 108 cfu/mL. The effectiveness of meropenem agreed with MICHVs for the 106 cfu/mL inoculum and with MICHIs or MICHVIs for the 108 cfu/mL inoculum. Strains characterized as resistant according to these values grew during meropenem exposure, and resistant mutants were selected. Our results suggest that MICHV-based parameters may be suitable for predicting antibacterial effects and the risk of resistance development when the inoculum is 106 cfu/mL, while MICHI- or MICHVI-based parameters are suitable for these purposes when the inoculum is 108 cfu/mL. Also, the correlation between resistance selection and the MICHI-based parameter was as high as one that corresponds with a mutant prevention concentration (MPC)-based parameter; this suggests that the MPC can be replaced by the more easily determined alternative parameter MICHI.

Food Insecurity at Tuberculosis Treatment Initiation Is Associated With Clinical Outcomes in Rural Haiti: A Prospective Cohort Study.

Tuberculosis is a leading cause of death worldwide, and food insecurity is known to negatively influence health outcomes through multiple pathways. Few studies have interrogated the relationship between food insecurity and tuberculosis outcomes, particularly independent of nutrition. We conducted a prospective cohort study of adults initiating first-line treatment for clinically suspected or microbiologically confirmed drug-sensitive tuberculosis at a rural referral center in Haiti. We administered a baseline questionnaire, collected clinical data, and analyzed laboratory samples. We used logistic regression models to estimate the relationship between household food insecurity (Household Hunger Scale) and treatment failure or death. We accounted for exclusion of patients lost to follow-up using inverse probability of censoring weighting and adjusted for measured confounders and nutritional status using inverse probability of treatment weighting. We enrolled 257 participants (37% female) between May 2020 and March 2023 with a median age (interquartile range) of 35 (25-45) years. Of these, 105 (41%) had no hunger in the household, 104 (40%) had moderate hunger in the household, and 48 (19%) had severe hunger in the household. Eleven participants (4%) died, and 6 (3%) had treatment failure. After adjustment, food insecurity was significantly associated with subsequent treatment failure or death (odds ratio 5.78 [95% confidence interval, 1.20-27.8]; P = .03). Household food insecurity at tuberculosis treatment initiation was significantly associated with death or treatment failure after accounting for loss to follow-up, measured confounders, and nutritional status. In addition to the known importance of undernutrition, our findings indicate that food insecurity independently affects tuberculosis treatment outcomes in Haiti.

Clinical Relevance of Human Immunodeficiency Virus Low-level Viremia in the Dolutegravir era: Data From the Viral Load Cohort North-East Lesotho (VICONEL).

Human immunodeficiency virus low-level viremia (LLV) is associated with subsequent treatment failure at least with non nucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral therapy. Data on implications of LLV occurring under dolutegravir, which has largely replaced NNRTIs in Africa, are scarce, however. We included adults with human immunodeficiency virus in Lesotho who had ≥2 viral loads (VLs) taken after ≥6 months of NNRTI- or dolutegravir-based antiretroviral therapy. Within VL pairs, we assessed the association of viral suppression (<50 copies/mL) and low- and high-range LLV (50-199 and 200-999 copies/mL, respectively) with virological failure (≥1000 copies/mL) using a mixed-effects regression model. Participants could contribute VLs to the NNRTI and the dolutegravir group. Among 18 550 participants, 12 216 (65.9%) were female and median age at first VL included was 41.2 years (interquartile range, 33.4-51.5). In both groups, compared with a suppressed VL, odds of subsequent virological failure were higher for low-range LLV (NNRTI: adjusted odds ratio; 95% confidence interval: 1.9; 1.4-2.4 and dolutegravir: 2.1; 1.3-3.6) and high-range LLV (adjusted odds ratio; 95% confidence interval, 4.2; 3.1-5.7 and 4.4; 2.4-7.9). In the dolutegravir era, LLV remains associated with virological failure, endorsing the need for close clinical and laboratory monitoring of those with a VL ≥50 copies/mL.

The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib.

PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib. Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.

Complications During Root Canal Shaping: A Survey Among Dentists in Morocco

Introduction: Endodontic therapy is a complex procedure that requires a high level of precision due to the intricacies of the root canal system. Despite advancements in endodontic tools and techniques, incidents such as instrument fractures, dentinal plugs, false routes, and root perforations can occur when best practice recommendations are not adhered to. These complications pose a significant public health concern as they can lead to potentially severe infectious complications and ultimately result in endodontic treatment failure. The aim of this study is to elucidate the causes of endodontic complications, particularly during the root canal shaping stage, and to identify strategies for their prevention.Materials and Methods: A cross-sectional, analytical, descriptive, and unidirectional study was conducted on a randomly selected sample of 300 private dentists in Casablanca. The questionnaires were completed anonymously, and statistical analyses were performed using SPSS software. The discussion will be enriched through a comprehensive literature search of major databases, complemented by a series of clinical cases illustrating these complications and the means by which they can be mitigated.Results: The study reveals that 91% of dentists encountered complications during endodontic therapy, with 284 dentists (94.98%) experiencing complications during root canal shaping. The most prevalent complication was instrument fracture, reported by 235 dentists (82.75%). Key contributing factors to these complications included forced file passage, non-adherence to the instrumental sequence, and absence or inadequacy of irrigation. However, these incidents can be averted by adhering to a meticulous treatment protocol and respecting the various steps critical to the success of root canal shaping.Conclusion: In conclusion, there exists a disparity between recommended best practices and the current practices in the field of endodontics, which can lead to multiple complications and subsequent endodontic treatment failures.

Defeating the Hidden Foe: Antibiotic Therapy and Clinical Outcomes of Cutibacterium acnes Spinal Implant Infections.

Cutibacterium acnes can cause spinal implant infections. However, little is known about the optimal medical management and outcomes of C. acnes spinal implant infections (CSII). Our study aims to describe the management of patients with CSII and evaluate the clinical outcomes. We performed a retrospective cohort study of patients aged 18 years or older who underwent spinal fusion surgery with instrumentation between January 1, 2011, and December 31, 2020, and whose intraoperative cultures were positive for C. acnes. The primary outcome was treatment failure based on subsequent recurrence, infection with another organism, or unplanned surgery secondary to infection. There were 55 patients with a median follow-up (interquartile range) of 2 (1.2-2.0) years. Overall, there were 6 treatment failures over 85.8 total person-years, for an annual rate of 7.0% (95% CI, 2.6%-15.2%). Systemic antibiotic treatment was given to 74.5% (n = 41) of patients for a median duration of 352 days. In the subgroup treated with systemic antibiotics, there were 4 treatment failures (annual rate, 6.3%; 95% CI, 1.7%-16.2%), all of which occurred while on antibiotic therapy. Two failures occurred in the subgroup without antibiotic treatment (annual rate, 8.8%; 95% CI, 1.1%-31.8%). Our study found that the estimated annual treatment failure rate was slightly higher among patients who did not receive antibiotics. Of the 6 failures observed, 4 had recurrence of C. acnes either on initial or subsequent treatment failures. More studies are warranted to determine the optimal duration of therapy for CSII.

Outcomes of Nonoperatively Treated Vancouver B1 Fractures: Is Failure Common?

BackgroundPeriprosthetic fractures (PPFx) are a severe complication of total hip and hemiarthroplasty. Surgical treatment is typically performed but can result in major morbidity. Nonoperative PPFx management may provide a successful treatment alternative in select patients. MethodsVancouver B1 PPFx patients treated over a 10-year period were identified. Patient demographic data were retrospectively recorded. Injury and postoperative radiographs were reviewed. There were 48 patients who met the study criteria. Patients were divided into operative and nonoperative comparative cohorts. Outcome comparisons between the 2 cohorts included 1-year mortality, unplanned surgery within 24 months of injury, fracture union rate, and return to preinjury ambulation status. ResultsThere was no difference in 1-year mortality between the nonoperative and operative cohorts (17 versus 8%; P = .32). We found no significant difference in unplanned surgery between the nonoperative and operative groups (8.7 versus 12%; P = .71), fracture union (100 versus 96%, P = .34), or return to ambulation status (86 versus 91%; P = .86). Nonoperative fractures were minimally displaced and within the metaphyseal region of the proximal femur without stem subsidence. Nonoperative fractures with subsequent treatment failure had initial fracture extension closer to the tip of the stem compared to successfully treated nonoperative fractures (5.5 versus 10.2 centimeters; P = .02). ConclusionSelect nonoperatively treated patients had infrequent need for unplanned surgery, high union rate, and return to their preinjury ambulation status. Nonoperative management is not appropriate for all Vancouver B1 PPFx, but those patients who have minimally displaced meta-diaphyseal fractures and partial remaining distal fixation can be successfully treated.

P676 Intestinal ultrasound accurately predicts therapy failure in Crohn's disease patients during a biologics-induced remission

Abstract Background Intestinal Ultrasound (IUS) is a non-invasive modality that can assess disease activity, complications, and treatment follow-up in Crohn's disease (CD) patients. IUS is reliable, patient-friendly, and allows frequent monitoring of disease activity. While 3mm bowel wall thickness (BWT) was repeatedly found to correlate with intestinal inflammation, whether this threshold also best predicts clinically relevant future outcomes is still largely unknown. We aim to investigate the role of IUS to predict the risk of therapy failure in biologics-treated CD patients in clinical remission. Methods Our analysis included a retrospective cohort of CD patients in clinical remission (HBI≤4) induces by biologic drugs, who underwent IUS 12 (±2) months after induction. We examined the correlation of IUS activity parameters with future therapy failure (defined as drug discontinuation, dose escalation, new corticosteroid use, CD-related hospitalization, or surgery). Results A total of 57 patients (58% male), with ileal (65%) or ileocolonic (35%) CD, on biological therapy (28% infliximab, 51% adalimumab, 10.5% vedolizumab, 10.5% ustekinumab) were included. Therapy failure occurred in 54.3% (32.2% drug discontinuation, 45.2% dose escalation, 16.2% corticosteroid use and 6.4% hospitalization) during a median follow-up of 12 (IQR 5-22) months after IUS. Of all IUS parameters examined, therapy failure was associated only with increased BWT; BWT &amp;gt; 5mm (hazard ratio (HR) 2.3 [confidence interval (CI) 1.03-5.3], p= 0.041). Interestingly, there was risk plateauing with increased BWT above this cutoff (&amp;gt;5.5 mm (HR 2.2 [CI 1-5.10], p=0.048); &amp;gt;6mm (HR 2.6 [CI 1.17-6.12], p=0.019); &amp;gt;6.5 mm (HR 2.5 [CI 1.08-5.83], p=0.032)) (Figure 1). A BWT cutoff of 3mm could not discriminate patients with future treatment failure. Conclusion Our findings suggest that BWT of &amp;gt; 5 mm during clinical remission can predict subsequent treatment failure in CD patients treated with biologics. Our results support the use of IUS in monitoring CD during remission, and may point to a novel threshold predicting disease reactivation.

Comparison of Clinical Outcomes between Transplant and Non-Transplant Therapies in Myelofibrosis Following Failure of First-Line JAK-Inhibitor

Background: JAK-inhibitor (JAKi) therapy can improve MF-related symptom burden and quality of life (QOL) for patients with myelofibrosis (MF). Clinical benefit is variable with most patients experiencing failure of firstline (1L) JAKi therapy by 3 years and subsequent survival of 11-16 months. At our centre, hematopoetic stem cell transplant (HCT) is considered in patients after 1L JAKi failure who are fit for transplant. Many patients do not prefer HCT despite donor availability due to concerns of adverse impact on QOL and mortality. The approval of fedratinib and pacritinib as second-line (2L) JAKi and ongoing development of novel therapies provide new options for patients with JAKi failure. Data on clinical outcomes with or without HCT following 1L JAKi failure are limited, with prospective studies logistically challenging in a rare disease. Aims: To compare the overall (OS) and transformation-free (TFS) survival following 1L JAKi failure in chronic-phase MF patients who receive HCT or best available non-transplant therapy (BAT). Methods: We conducted a retrospective review of patients with MF from the Princess Margaret prospective MPN registry (NCT02760238) treated with 1L JAKi from 2012-2021. Patients were included in the study if they had failure of 1L JAKi therapy as defined by Canadian MPN Group criteria, and excluded if they were not fit for HCT due to: age >70 years, death ≤8 weeks of JAKi failure, accelerated/blast phase (AP/BP), active second cancer, prohibitive performance status or co-morbidities. Patients included in the BAT group received 2L JAKi, clinical trial novel agent (alone or in combination with JAKi), splenectomy, transfusion support, or other non-transplant therapy. Survivals were calculated from time of JAKi-failure to last follow-up, death (OS), or transformation to AP/BP (TFS). Results: Of the 641 patients with MF in our database, 323 (50.4%) were treated with 1L JAKi and 88 considered HCT-eligible following JAKi failure. The 1L JAKi was ruxolitinib in 75 (85%) patients and momelotinib in 13 (15%). Patterns of JAKi failure were: suboptimal/loss of spleen response n=57 (65%), cytopenias n=27 (31%), non-hematologic toxicity n=4 (4%). From time of JAKi failure the median [range] follow-up was 21.0 [3-126] months. Following 1L JAKi failure 41 (47%) patients underwent HCT; and 47 (53%) received BAT including 2L JAKi (fedratinib n=7, momelotinib n=6, ruxolitinib n=3, pacritinib n=3), investigational agent added to ruxolitinib (n=3), continuation of 1L JAKi (n=18), splenectomy (n=6), and splenic radiation (n=1). Two patients in the BAT group underwent salvage HCT following failure of subsequent treatment. In the HCT group 8 patients received bridging 2L treatment (fedratinib n=4, ruxolitinib n=2, splenectomy n=2). At time of JAKi failure the HCT cohort was younger (median [range] 60[38-69]y vs. 65[49-70]y, P=0.002), had smaller palpable spleen size (10[0-26] vs. 17[0-35]cm, P<0.001), less frequent constitional symptoms (15% vs. 35%, P=0.03), and greater proportion of low/int-1 age-adjusted DIPSS (aaDIPSS 59% vs 28%, P=0.02). There was no observed significant differences in ECOG status, blood/BM blast counts, RBC transfusion needs, or pattern of failure. The median [95% confidence interval] OS(Fig 1) and TFS (Fig 2) were 51 [23-Not Reached] and 51 [23-89] months respectively in the HCT group; and 24 [16-46] and 21 [14-34] months in the BAT group. Survival rates in two arms were similar up to 12 months after JAKi failure (OS 76% vs 78%; TFS 76% vs. 72%), but began to diverge in favour of HCT at 24 months (OS 65% vs. 47%, TFS 65% vs. 43%) and 36 months (OS 56% vs. 35%, TFS 56% vs. 31%). Multivariable Cox proportional hazards model adjusted for age and aaDIPSS did not observe significant benefit for HCT (OS Hazard Ratio 0.68 [95%CI 0.37-1.27]; TFS 0.60 [0.32-1.1]). At the last follow up, there were 21 (51%) and 28 (59%) deaths recorded in the HCT and BAT arms, respectively. The main causes of death were transplant-related complications (n=14) and relapsed/progressive disease (n=4) in the HCT cohort; and progression of MF with (n=11) or without (n=12) AP/BP transformation in the BAT arm. Despite a large cohort of JAKi-treated patients, the number of HCT-eligible patients is small and is the main limitation of this study. Conclusion: Patients with MF and failure of first line JAKi managed with HCT or BAT have similar short-term outcomes, but trend towards better OS and TFS with HCT after 12 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First line antiretroviral treatment failure and its association with drug substitution and sex among children in Ethiopia: systematic review and meta-analysis

Antiretroviral Treatment (ART) has significantly decreased HIV-related morbidity and mortality among children despite the issue of drug resistance and subsequent treatment failure appearing as a challenge. Different studies have been conducted in Ethiopia regarding the prevalence of first-line ART failure among children but the magnitudes of these studies were inconsistent and had great variability. This review aimed to estimate the pooled prevalence of first line ART failure among children and its association with drug substitution and sex of children among first-line ART users in Ethiopia. The review was conducted using both published and unpublished studies until September 2020 in Ethiopia. MEDLINE, PubMed, Hinari, Web of Science, Google Scholar, Africa journal online (AJOL), Open gray literature, and online repository articles were searched. The quality of individual studies was assessed by Joanna Briggs Institute's (JBI) critical appraisal checklist. The statistical analysis was done by STATA-14 software and a random effect model was used. Heterogeneity was assessed using forest plot Cochrane Q–test and I-squared statistic. Publication bias was checked by using a funnel plot and Egger’s and Begg’s statistical tests. The interpretation was made by an odds ratio and with their respective 95% confidence intervals. The heterogeneity rate was 90% and Begg’s and Egger’s for publication bias were insignificant with p-values of 0.89 and 0.11 respectively. The pooled prevalence of pediatric first line ART failure in Ethiopia was 14.98% (95% CI 11.74, 18.21). Subgroup analysis showed that the highest failure rate was virological (9.13%). Female children had 1.4 times more risk of first-line ART failure (OR = 1.42; 95% CI 1.08, 1.85). First-line ART failure among children in Ethiopia is considerably high. Being female increases the likelihood of facing first line ART failure. More attention should be given to female children.

Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors.

Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status.

P709: CLINICAL OUTCOME OF ASCIMINIB TREATMENT IN A REAL-WORLD MULTI-RESISTANT CML PATIENT POPULATION.

Background: Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) tyrosine kinase inhibitor (TKI). Asciminib was found to have superior efficacy compared to bosutinib in patients (pts) intolerant or refractory to ≥2 currently registered TKI with good tolerability. While awaiting its EMA approval, asciminib is made available by Novartis to pts with high clinical need in an early access programme (EAP) in The Netherlands. Aims: We aimed to assess treatment outcomes in this nationwide patient cohort. Methods: Dutch hematologists who treated CML pts in the asciminib EAP were asked to provide clinical data of consenting pts. Pts were included if ≥18 years and treated in this asciminib EAP, thus outside clinical trials. Treatment failure was defined as progression to advanced stage disease (AP/BC), not reaching a complete cytogenetic response or BCR-ABL1 <1%IS (CCYR/MR2.0) (=primary) or losing previously achieved responses (=secondary). Event-free survival (EFS) was defined as time from asciminib start until allogeneic stem cell transplantation (SCT), progression to AP/BC or death; whatever came first. Responses were assessed with the cumulative incidence competing risk (CICR) method considering the competing event of TKI discontinuation for any cause. Results: All hematologists agreed to participate and 53 out of 56 pts from 14 medical centers consented and were included. Most pts (72%) had been exposed to ≥3 TKIs prior to asciminib. The majority (79%) started with asciminib because of multi-resistance (with or without intolerance) including 15 pts with primary ponatinib-failure, 15 pts harboring the T315I mutation and 3 pts with compound mutations. Two pts were treated with asciminib post-SCT and were excluded from response analyses. Median asciminib exposure was 7 months (IQR 3-16). Frequently reported adverse events (AE) were cytopenia and folliculitis, classified as probably related to asciminib and manageable generally without dose modification. Only one pt definitely discontinued asciminib due to persistent anemia, but in the context of also a failing response. Two vascular events were reported, one recurrent TIA therefore classified as unrelated and one NSTEMI classified as possibly related to asciminib. Sixteen pts discontinued asciminib, mostly because of treatment failure (primary n=8, secondary n=2) or proceeding to SCT (n=5). Six out of 7 pts with AP/BC discontinued asciminib within 6 months because of treatment failure/SCT. The CI of maintaining or reaching CCYR/MR2.0 and MMR by 6 months for CP pts were 60% and 44%, respectively. Of note, only one out of 10 pts in CP with primary ponatinib-failure reached MR2.0 and none of these patients reached MMR. However, CP pts with secondary ponatinib-failure responded well with CCYR/MR2.0 or better in 78% (7/9). During asciminib treatment 5 pts progressed to advanced stage disease, 9 pts eventually underwent SCT and 7 pts died of whom 6 with a CML-related cause. Overall survival and EFS were 87% and 72%, with a median follow-up time of 10 and 8 months, respectively. Image:Summary/Conclusion: Our results show that asciminib is a well-tolerated novel treatment option for CML with adequate response rates, even in a heavily pretreated multi-resistant patient cohort. Most frequently reported AEs were manageable cytopenia and folliculitis. No patient discontinued asciminib solely due to intolerance. The CI of maintaining or reaching MR2.0/CCYR at 12 months was 57%. In our cohort, prior primary ponatinib-failure generally heralded subsequent asciminib treatment failure, both in the presence and absence of a T315I-mutation.

Enhancing the Response Rate to Recombinant Uricases in Patients with Gout

Refractory, or uncontrolled, gout is a chronic, progressive, inflammatory arthropathy resulting from continued urate deposition after failed attempts to lower serum uric acid below the therapeutic threshold with oral urate-lowering therapies such as allopurinol and febuxostat. Recombinant uricase is increasingly being used to treat refractory gout; however, the immunogenicity of uricase-based therapies has limited the use of these biologic therapies. Antidrug antibodies against biologic therapies, including uricase and PEGylated uricase, can lead to loss of urate-lowering response, increased risk of infusion reactions, and subsequent treatment failure. However, co-therapy with an immunomodulator can attenuate antidrug antibody development, potentially increasing the likelihood of sustained urate lowering, therapy course completion, and successful treatment outcomes. This review summarizes evidence surrounding the use of immunomodulation as co-therapy with recombinant uricases.

Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.

Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.

Lactic acid gel versus metronidazole for recurrent bacterial vaginosis in women aged 16 years and over: the VITA RCT.

Bacterial vaginosis is a common and distressing condition associated with serious comorbidities. Antibiotic treatment is usually clinically effective in the short term, but recurrence is common and side effects can occur. The objective is to assess whether or not intravaginal lactic acid gel is clinically effective and cost-effective for treating recurrent bacterial vaginosis compared with oral metronidazole (Flagyl, Sanofi). This was an open-label, multicentre, parallel-arm, randomised (1 : 1) controlled trial. This took place in one general practice and 19 sexual health centres in the UK. Women aged ≥ 16 years with bacterial vaginosis symptoms and one or more episode(s) within the past 2 years took part. The interventions were 5 ml of intravaginal lactic acid gel taken once daily for 7 days (intervention) or 400-mg oral metronidazole tablets taken twice daily for 7 days (control). The primary outcome was the resolution of bacterial vaginosis symptoms 14 days after randomisation. The secondary outcomes were time to first recurrence of symptoms; number of recurrences and treatment courses over 6 months; microbiological resolution on microscopy of vaginal smears at week 2; time to resolution of symptoms; tolerability, adherence and acceptability of the treatment; prevalence of concurrent sexually transmitted infections; quality of life; and cost-effectiveness. Recruitment stopped prior to reaching the target of 1900 participants on recommendation from the Data Monitoring Committee and Trial Steering Committee after a planned review of the results indicated that the research question had been answered. Overall, 518 participants were randomised and primary outcome data were available for 409 participants (79%; 204 in the metronidazole arm, 205 in the lactic acid gel arm). Participant-reported symptom resolution at week 2 was higher with metronidazole (143/204; 70%) than with lactic acid gel (97/205; 47%) (adjusted risk difference -23.2%, 95% confidence interval -32.3% to -14.0%). Recurrence in 6 months in a subset of participants who had initial resolution and were available for follow-up was similar across arms (metronidazole arm: 51/72, 71%; lactic acid gel arm: 32/46, 70%). A higher incidence of some side effects was reported with metronidazole than with lactic acid gel (nausea 32% vs. 8%; taste changes 18% vs. 1%; diarrhoea 20% vs. 6%, respectively). At week 2, the average cost per participant with resolved symptoms was £86.94 (metronidazole), compared with £147.00 (lactic acid gel). Some participants preferred using lactic acid gel even if they perceived it to be less effective than metronidazole. Loss to follow-up for collection of the primary outcome data was 21% and was similar in both arms. There is a risk of bias owing to missing outcome data at 3 and 6 months post treatment. A higher initial response was seen with metronidazole than with lactic acid gel, but subsequent treatment failure was common with both. Lactic acid gel was less cost-effective than metronidazole. In general, women disliked taking repeated courses of metronidazole and preferred lactic acid gel, even when they were aware that it was less likely to provide symptom resolution. In the absence of effective curative therapy, further evaluation of non-antibiotic treatments to control the symptoms of recurrent bacterial vaginosis is required to improve quality of life for these patients. Further microbiological analysis of vaginal samples would be useful to identify additional factors affecting response to treatment. Current Controlled Trials ISRCTN14161293. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 2. See the NIHR Journals Library website for further project information.

First-line corticosteroids for Kawasaki disease: Pulse versus multiple dose.

Kawasaki disease (KD) can result in severe coronary artery abnormalities (CAAs). Corticosteroids added to initial standard intravenous immunoglobulin (IVIG) treatment may decrease the risk for these complications. Different corticosteroid regimens (single-day high dose pulse vs multiple lower doses) may contribute to the discrepant results of prior studies. Using data from the 22nd, 23rd , and 24th Japanese nationwide KD surveys (2011-2016), we identified KD patients who did not have CAAs at first presentation and who were treated with either pulse or multiple-dose corticosteroids as part of their initial treatment. Occurrence of subsequent CAAs and treatment failure were compared between the treatment regimens and adjusted odds ratios were calculated controlling for sex, age group, illness day at first treatment, survey, and recurrent KD. There were 782 KD patients who received pulse corticosteroid treatment and 4,817 who received multiple dose treatment. Patients receiving multiple dose treatment were less likely to develop CAAs (5.5% vs 8.3%, OR 0.64; 95% CI: 0.48-0.85) or treatment failure (21.4% vs 41.6%; OR: 0.38; 95% CI: 0.33-0.45). Adjusted analyses showed similar protective effects of multiple-dose treatment against CAAs (OR: 0.67, 95% CI: 0.51-0.90) and treatment failure (OR: 0.39, 95% CI: 0.33-0.46). Multiple-dose corticosteroid combination treatment resulted in substantially improved outcomes in KD patients compared to pulse treatment. For patients who may be at elevated risk of treatment failure or CAA, use of multiple-dose corticosteroids in conjunction with IVIG is likely to provide considerable clinical benefit.

Short-course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide.

IntroductionShort‐course preventive therapy with 1‐month course of daily administration of isoniazid (300‐mg) plus rifapentine (600‐mg) (1HP) and 3‐month course of weekly administration of isoniazid (900‐mg) plus rifapentine (900‐mg) (3HP) has higher completion rates than 9‐month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).MethodsPLWH testing positive by interferon‐gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.ResultsFrom November 2019 to December 2020, 48 PLWH with LTBI were enrolled. One participant (2.1%) discontinued 1HP on day 15 due to fever and generalized rashes with PVL of 72 copies/ml, which was <50 copies/ml in three subsequent determinations while on BIC/FTC/TAF over the 12 months of follow‐up. The percentages of BIC trough plasma concentrations above the protein‐adjusted 95% effective concentration (paEC95 = 162 ng/ml) were 56.3% and 37.0% on days 15 and 29, respectively. The percentage of PVL <200 copies/ml was 91.7% on day 15, 97.8% on day 29 and 100% at both months 3 and 6. After a median observation of 52 weeks (interquartile range, 51–55), all participants continued BIC/FTC/TAF with a median PVL of 20 copies/ml (range 20–331). Except for the participant who discontinued 1HP because of allergic reactions, none of the participants had relevant symptoms or increases of the cytokine levels assessed between baseline and days 15 and 29 of 1HP.ConclusionsBIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.