Initial Regimen Research Articles

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

Frequency Variation and Dose Modification of Benznidazole Administration for the Treatment of Trypanosoma cruzi Infection in Mice, Dogs, and Nonhuman Primates.

Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.

Efficacy, Convenience, Safety and Durability of DTG-Based Antiretroviral Therapies: Evidence from a Prospective Study by the Italian MaSTER Cohort.

Background: Dolutegravir (DTG) is recommended by international guidelines as a main component of an optimal initial regimen of cART (combination antiretroviral treatment) in people living with HIV (PLWH) and in case of switching for failure or optimization strategies. However, studies on the performance of DTG-containing regimens and indications for switching therapies in the long term are sparse. The purpose of this study was to evaluate prospectively the performance of DTG-based regimens, using the metrics of "efficacy", "safety", "convenience" and ''durability'', among a nationally representative cohort of PLWH in Italy. Methods: We selected all PLWH in four centers of the MaSTER cohort who initiated a DTG-based regimen either when naïve or following a regimen switch between 11 July 2018 and 2 July 2021. Participants were followed until the outcomes were recorded or until the end of the study on 4 August 2022, whichever occurred first. Interruption was reported even when a participant switched to another DTG-containing regimen. Survival regression models were fitted to evaluate associations between therapy performance and age, sex, nationality, risk of HIV transmission, HIV RNA suppression status, CD4+ T-cell count, year of HIV diagnosis, cART status (naïve or experienced), cART backbone and viral hepatitis coinfection. Results: There were 371 participants in our cohort who initiated a DTG-based cART regimen in the time frame of the study. The population was predominantly male (75.2%), of Italian nationality (83.3%), with a history of cART use (80.9%), and the majority initiated a DTG-based regimen following a switch strategy in 2019 (80.1%). Median age was 53 years (interquartile range (IQR): 45-58). Prior cART regimen was based mostly on a combination of NRTI drugs plus a PI-boosted drug (34.2%), followed by a combination of NRTIs plus an NNRTI (23.5%). Concerning the NRTI backbone, the majority comprised 3TC plus ABC (34.5%), followed by 3TC alone (28.6%). The most reported transmission risk factor was heterosexual intercourse (44.2%). Total interruptions of the first DTG-based regimen were registered in 58 (15.6%) participants. The most frequent reason for interruption was due to cART simplification strategies, which accounted for 52%. Only 1 death was reported during the study period. The median time of total follow-up was 556 days (IQR: 316.5-722.5). Risk factors for poor performance of DTG-containing-regimens were found to be: a backbone regimen containing tenofovir, being cART naïve, having detectable HIV RNA at baseline, FIB-4 score above 3.25 and having a cancer diagnosis. By contrast, protective factors were found to be: higher CD4+ T-cell counts and higher CD4/CD8 ratio at baseline. Conclusion: DTG-based regimens were used mainly as a switching therapy in our cohort of PLWH who had undetectable HIV RNA and a good immune status. In this type of population, the durability of DTG-based regimens was maintained in 84.4% of participants with a modest incidence of interruptions mostly due to cART simplification strategies. The results of this prospective real-life study confirm the apparent low risk of changing DTG-containing regimens due to virological failure. They may also help physicians to identify people with increased risk of interruption for different reasons, suggesting targeted medical interventions.

Non-opioid analgesics for procedural pain in neonates.

Non-opioid analgesics for procedural pain in neonates.

Comparative Safety and Changes in Immunologic and Virologic Parameters of Dolutegravir versus Efavirenz-Based Antiretroviral Therapies Among HIV Patients: A Retrospective Cohort Study.

In combination with other two antiretroviral drugs, an efavirenz (EFV) or dolutegravir (DTG)-based regimen is the treatment of choice for human immunodeficiency virus (HIV) infection. This study aimed to determine the safety and changes in immunologic and virologic parameters of DTG compared with EFV-based ART as first-line HIV treatment among HIV patients. A retrospective hospital-based cohort study was carried out from September 1, 2019 to August 30, 2020 at HIV clinics of three selected hospitals in North-West-East Ethiopia, Amhara Region. All HIV patients ≥3 years old, who had been on either DTG or EFV-based combination anti-retroviral therapy (cART), and had detectable viral load (VL) were included. Descriptive and multivariate Cox regression analyses were used. Overall, 990 HIV patients were included in the analysis (DTG n=694, EFV n=296). A VL of <50 copies/mL was observed in 69% of patients in the DTG group and 66% in the EFV group (crude hazard ratio [CHR] =1.28, 95% CI: 1.08-1.51; p=0.004). Out of the total, 289 (42%) of the patients in the DTG group reported adverse drug events (ADEs) compared with 147 (50%) in the EFV group (p=0.020). Younger age, opportunistic infections (OIs), bed-ridden condition, no prophylaxis for OIs, low baseline cluster of differentiation 4 (CD4) count, high baseline VL, poor adherence, and ADEs were predictors of poor survival, and younger age, OIs, low baseline CD4, DTG-based initial regimen, poor adherence with cART, naïve treatment history, and student job type were predictors of poor safety outcomes. The DTG-based regimen demonstrates an improved viral suppressionand CD4 cell recovery, and better safety profile compared with the EFV-based regimen for the treatment of HIV-infected patients. A baseline CD4+ T-cell count <200 cells/mm3, OIs, and poor adherence with therapy were factors associated with poor survival and safety outcomes. HIV patients with these risk factors should be treated and monitored regularly.

Excess mortality and associated factors among people living with HIV initiating highly active antiretroviral therapy in Luzhou, China 2006–2020

BackgroundTo estimate crude mortality, excess mortality, and standardized mortality rates (SMR) among people living with HIV (PLHIV) initiating highly active antiretroviral therapy (HAART) in Luzhou, China 2006–2020, and assess associated factors.MethodsPLHIV initiating HAART in the HIV/AIDS Comprehensive Response Information Management System (CRIMS) in Luzhou, China 2006–2020 were included in the retrospective cohort study. The crude mortality, excess mortality, and SMR were estimated. Multivariable Poisson regression model was used for analyzing risk factors associated with excess mortality rates.ResultsThe median age among 11,468 PLHIV initiating HAART was 54.5 years (IQR:43.1–65.2). The excess mortality rate decreased from 1.8 deaths/100 person-years (95% confidence interval [CI]:1.4–2.4) in 2006–2011 to 0.8 deaths/100 person-years (95%CI:0.7–0.9) in 2016–2020. SMR decreased from 5.4 deaths/100 person-years (95%CI:4.3–6.8) to 1.7 deaths/100 person-years (95%CI:1.5–1.8). Males had greater excess mortality with the eHR of 1.6 (95%CI:1.2–2.1) than females. PLHIV with CD4 counts ≥ 500 cells/μL had the eHR of 0.3 (95%CI:0.2–0.5) in comparison to those with CD4 counts < 200 cells/μL. PLHIV with WHO clinical stages III/IV had greater excess mortality with the eHR of 1.4 (95%CI:1.1–1.8). PLHIV with time from diagnosis to HAART initiation ≤ 3 months had the eHR of 0.7 (95%CI:0.5–0.9) compared to those with time ≥ 12 months. PLHIV with initial HAART regimens unchanged and viral suppression had the eHR of 1.9 (95%CI:1.4–2.6) and 0.1 (95%CI:0.0–0.1), respectively.ConclusionsThe excess mortality and SMR among PLHIV initiating HAART in Luzhou, China decreased substantially from 2006 to 2020, but the mortality rate among PLHIV was still higher than general population. PLHIV who were male, with baseline CD4 counts less than 200 cells/μL, WHO clinical stages III/IV, time from diagnosis to HAART initiation ≥ 12 months, initial HAART regimens unchanged, and virological failure had a greater risk of excess deaths. Early and efficient HAART would be significant in reducing excess mortality among PLHIV.

Recent Advances in the Management of Small Cell Carcinoma of the Uterine Cervix.

Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a rare disease characterized by a higher incidence of lymphatic invasion, metastasis, and recurrence compared to the squamous cell carcinoma and adenocarcinoma subtypes. Furthermore, it is prone to early distant metastasis and has a poor prognosis. Chemotherapy has an important role in the management of cervical SCNEC. The effective treatment schemes for early-stage SCNEC are local treatment with radical surgery and systemic chemotherapy. However no standard treatment regimen exists because of a rare disease. We reviewed previous reports to determine whether etoposide/platinum, which is used for histopathologically similar small cell carcinoma of the lung, is an appropriate initial chemotherapy regimen for SCNEC of the cervix. In this review the Cochrane library sources, ClinicalTrials.gov, Web of Silence, PubMed and search engine of Google scholar were searched for all interventional studies, reviews, case reports and meta-analyses published in 1997-2021. Etoposide/platinum (EP) is the most commonly used regimen and paclitaxel/carboplatin is the second most common, used as a part of multimodality therapy for SCNEC of the cervix in most studies. Cisplatin/vincristine/bleomycin, cisplatin/irinotecan, cisplatin/ifosfamide/etoposide were also reported in concurrence with EP; however no clinical trials are dedicated to SCNEC. Etoposide and platinum tend to have a better prognosis compared to other regimens used for other subtypes of cervical cancer. For recurrent cervical SCNEC, treatment options for patients are very limited. The application of molecular testing for targeted mutations may suggest potential future therapies that may be useful in this disease.

Epidemiology and mortality predictors for severe childhood community-acquired pneumonia in ICUs: A retrospective observational study.

To identify the epidemiology and mortality predictors of severe childhood community-acquired pneumonia (CAP) and evaluate the influence of medications on clinical outcomes in the real world. We conducted a multicenter retrospective observational study among children aged ≤5 years with severe CAP, separately comparing the detailed information between those who experienced in-hospital death and those who survived in three different age groups. A multivariate logistic regression model was used to determine mortality predictors. A total of 945 children were recruited: 341 young children aged 2-59 months, 47 infants aged 29 days to 2 months, and 557 neonates aged less than 28 days. A total of 88 deaths occurred (9.3%). There was low adherence to antimicrobial guidelines in the group aged 2-59 months, and carbapenems widely served as initial empirical regimens. However, analysis of all three age groups showed that the efficacy of antibacterial drugs with initial empirical selection grades higher than those recommended by the guidelines was not better than that of antibacterial drugs with grades recommended by the guidelines. In multivariate analyses, very severe pneumonia (odds ratio (OR): 3.48; 95% confidence interval (CI): 1.36-8.93), lower birth weight (OR: 4.64; 95% CI: 1.78-12.20), severe underweight (OR: 6.06; 95% CI: 2.34-15.63), mechanical ventilation (OR: 2.58; 95% CI: 1.00-6.62; OR: 15.63; 95% CI 3.25-76.92), a higher number of comorbidities (OR: 8.40; 95% CI: 1.89-37.04), comorbidities including anemia (OR: 5.24; 95% CI: 2.33-11.76) and gastrointestinal hemorrhage (OR: 3.79; 95% CI: 1.36-10.53), and the use of sedative-hypnotics (OR: 2.60; 95% CI: 1.14-5.95) were independent risk factors for death; infants treated with probiotics had a lower mortality rate (OR: 0.14; 95% CI: 0.06-0.33). Severe CAP remains a primary cause of death in children under 5 years of age. Clinical characteristics, comorbidities and medications are evidently associated with death. Importantly, we should pay particular attention to the identification of mortality predictors and establish prophylactic measures to reduce mortality.

Alternative initiations with 6-monthly paliperidone palmitate. A retrospective study

Introduction6-monthly paliperidone palmitate features an initiation regimen through 1-monthly paliperidone palmitate or 3-monthly paliperidone palmitate. Some patients do not have sufficient adherence to treatment and it is necessary at the clinical level to start directly with 6-monthly paliperidone palmitate. There is little clinical experience with these alternative initiations and through this work those that have been carried out for 12 months at the Hospital Universitario Infanta Elena are exposed.ObjectivesThe main objective of the study is to describe the alternative initiations performed with 6-monthly paliperidone palmitate in routine clinical practice, having opted for a regimen different from the standard for clinical reasons.MethodsA retrospective selection of patients will be made through non-probabilistic consecutive sampling, including all patients who have been administered 6-monthly paliperidone palmitate with a start different from the standard during the last 4 months. To do this, the electronic medical record will be used, first selecting the patients who have started 6-monthly paliperidone palmitate through the anonymized digital records and, later, including in the study only those who have followed an alternative initiation pattern. The variables studied will be the following: age, sex, diagnosis, dose of paliperidone palmitate, initiation regimen, consumption of toxic substances, absenteeism from 6-monthly paliperidone palmitate, and visits to the emergency room and admissions.ResultsThe study included a total of 20 patients (n: 20). 80% of the patients were male and 20% were female. The mean age was 39.7 years. 75% of the patients had an associated substance use disorder. The following alternate starting schedules were performed with biannual paliperidone palmitate: monthly paliperidone palmitate on days 1 and 8, and 6-monthly paliperidone palmitate on day 38 (n: 11); monthly paliperidone palmitate 150 mg together with semi-annual paliperidone palmitate both on day 1 (n: 5); biannual paliperidone palmitate on day 1 supplemented with oral paliperidone for 45 days (n:4). A total of 0 visits to the emergency department and 0 admissions were observed after the 6-monthly paliperidone palmitate regimen.ConclusionsAlternative initiations with 6-monthly paliperidone palmitate may be a useful and safe clinical alternative in patients with very low adherence who, due to clinical needs, require starting 6-monthly paliperidone palmitate earlier in order to guarantee adherence.Disclosure of InterestNone Declared

Alternative initiations with 6-monthly paliperidone palmitate. A descriptive study

Introduction 6-monthly paliperidone palmitate features an initiation regimen through 1-monthly paliperidone palmitate or 3-monthly paliperidone palmitate. Some patients don´t have sufficient adherence to treatment and it is necessary at the clinical level to start directly with 6-monthly paliperidone palmitte. There is une little clinical experience with these alternative initiations and throuht this work those that have been carried out for 12 months at the Rey Juan Carlos Hospital are exposed. Objectives The main objective of the study is to describe the alternative initations performed with 6-monthly paliperidone palmitate in routine clinical practice, having opted for a regimen different from the standard for clinical reasons. Methods A retrospective selection of patiens will be made throuht non-probabilistic consecutive sampling, including all patients who have benn administered 6-monthly paliperidone palmitate with a stard different form the standard during the last 6 months. To do his, the electronic medical record will be used, first selecting the patients who have started 6-monthly paliperidone palmitate through the anonymized digital records and, later, including in the study only those who have followed and alternative initiation pattern. The variables studied will be the following: age, sex, diagnosis, dose of paliperidone palmitate, initiation regimen, consumption of toxic substances, absenteeism from 6-monthly paliperidone palmitate, visits to the emergency room and admissions. Results The study included a total of 5 patients ( n:5). 80% of the patients were male and 20%were female. The mean age was 39.7 years. 80% of the patients had an associated substance use disorder. The following alternate sarting schedules were with biannual paliperidone palmitate: monthly paliperidone palmitate 150 mg together with semi-annual paliperidone palmitate both on day 1 ( n: 2) or monthly paliperidone palmitate 150 mg on day 1, monthly paliperidone palmitate 100 mg on day 5 and semi-annual paliperidone palmitate on day 12 ( n: 3 ). A total of 0 visits to the emergency department and 0 admissions were observed after the 6-monthly paliperidone palmitate regimen. Conclusions Alternative initations with 6-monthly paliperidone palmitate may be a useful and safe clinical alternative in patients with very low adherence who, due to clinical needs, require startin 6-monthly paliperidone palmitate earlier in order to guarantee adherence . Disclosure of Interest None Declared

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Abstract P540: Cardiovascular Disease Risk Factors and Antibody Response to COVID-19 Vaccination: The C4R Study

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI&gt;25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and &gt;35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

Abstract P394: Initial Antihypertensive Prescribing in Relation to Blood Pressure Among Medicaid and Medicare Recipients

Introduction: Early treatment for hypertension (HTN) portends better outcomes. However, few real-world studies have assessed initial antiHTN regimens and how they differ by baseline blood pressure (BP). We sought to compare initial treatment patterns, stratified by BP, between Medicaid and Medicare recipients. Methods: We performed a cross-sectional study of adults with newly-treated HTN in the One Florida+ Consortium(2012-2020) who had linked claims-EHR data from the treatment initiation visit. Eligible patients were Floridians with Medicaid or Medicare aged ≥18 years, with diagnosed HTN, who filled ≥1 first-line antiHTN class with no evidence of anti HTN fills during the year prior (in which continuous insurance enrollment was required). Baseline BP was categorized per current HTN guidelines, and logistic regression was used to estimate age-adjusted odds of combination vs. monotherapy, per 10 mmHg increase in systolic BP (SBP) or diastolic BP (DBP). Results: We included 2,902 patients (47% Medicaid, 53% Medicare); mean age was 44 (Medicaid) and 67 yrs(Medicare); 60% (64% and 56%, respectively) were women and 42% (57% and 29%, respectively) were Black. Initial antiHTN classes were similar comparing cohorts: ACEI, ARB and thiazide initiation varied little by BP category, in contrast to CCBs and β-blockers (Figure, panels A-B). In age-adjusted analyses, use of initial combination therapy was 40% more likely (OR, 1.40; 95% CI, 1.11, 1.76) among Medicare recipients and inversely related to BP category (panels C-D) among Medicare patients, in which each 10mmHg greater SBP (OR, 0.93; 95% CI, 0.88, 0.97) and DBP (OR 0.82; 95% CI, 0.75, 0.90) had lower odds of combination therapy. Among Medicaid recipients, only SBP associated with combination therapy (OR1.11; 95% CI, 1.03, 1.20). Conclusions: We observed similar initial class patterns among Medicaid &amp; Medicare recipients across baseline BP, but differential use of combination therapy was less likely at higher baseline BP in Medicare recipients, which contrasts current guidance.

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease

PurposeLoss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD.MethodsIn this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR.ResultsFollowing immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68–1.00) for regaining clinical remission, 0.87 (0.71–1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10−4).ConclusionImmunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

Early post-transplant leukopenia in heart transplant recipients and its impact on outcomes.

Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3×103 /μL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1×103 /μL vs. 6.9×103 /μL, p=.02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6%vs. 2.1%, p=.008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.

Utilization of metastatic hormone sensitive prostate cancer (mHSPC) treatment in a community oncology practice setting.

86 Background: Treatment options for mHSPC have continued to evolve. While androgen deprivation therapy (ADT) has been the backbone treatment, more recently early use of docetaxel and/or novel androgen receptor inhibitors (nARIs) has demonstrated improved clinical outcomes. This study assessed real-world treatment among mHSPC patients who received at least one line of therapy (LoT). Methods: A retrospective observational study utilizing de-identified health records from five Cancer Treatment Centers of America (CTCA) included patients with metastatic prostate cancer who were treated with ADT, docetaxel or nARIs at CTCA for 6+ months between 1/2015-3/2021. Treatment patterns were observed from first LoT to metastatic castration resistance, death, or lost-to-follow-up until 3/2022. LoT was defined as first to last date of active drug therapy, not including long-term hormone agonists. First LoT was defined as initial regimen with no new drugs added 30+ days after start date. Patient characteristics, proportion and duration of each LoT, and reasons for early discontinuation were gathered using structured data elements and chart abstraction. Results: The characteristics of the 523 patients in this study were as follows: mean (SD) age 62 (8) years, 60% white and 33% black, 53% with commercial insurance, 75% with ECOG 0-1, and 65% with bone metastasis at diagnosis. Median follow-up time was 2.9 years. The most common LoT 1 regimen was either ADT alone or ADT with first generation androgen receptor inhibitors (FGARI) (table below). 46% received a second and 15% received a third LoT. Mean (SD) duration of first and second active LoTs were 12 (11.8) and 10 (11.1) months, respectively. Among the 65% and 78% patients who discontinued therapy in LoT 1 and 2, respectively, the majority discontinued due to progression of disease (35% LoT 1 and 53% LoT 2) followed by patient choice (23% LoT 1 and 18% LoT 2). Conclusions: Despite recommendations from guidelines on early intensification of therapy in mHSPC, in this contemporary cohort we find that most patients received either ADT alone or ADT ± FGARI in LoT 1 while chemotherapy and nARIs were initiated predominantly in later lines. Most patients discontinued LoT 1 due to disease progression which may suggest undertreatment and need for improved outcomes. Further studies are needed to assess the factors associated with non-intensification of treatments. [Table: see text]

Treatment Strategy for Rifampin-Susceptible Tuberculosis

BackgroundTuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.MethodsIn this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin–linezolid and bedaquiline–linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points.ResultsOf the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin–linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline–linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin–linezolid strategy group, and 85 days in the bedaquiline–linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups.ConclusionsA strategy involving initial treatment with an 8-week bedaquiline–linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.)

Characterization of clinical outcomes among patients with advanced chromophobe renal cell carcinoma (ChRCC) treated with first-line immunotherapy (IO)-based regimens.

654 Background: IO-based regimens have demonstrated substantial efficacy in the management of metastatic clear-cell RCC (mccRCC), where they currently represent the standard of care. ChRCC has a dismal prognosis in the metastatic setting. Recent clinical trials evaluating IO-based regimens across non-ccRCC subtypes identified a preliminary poor response in advanced ChRCC, but were limited by low sample sizes. We sought to comprehensively evaluate the outcomes of patients with ChRCC treated with IO-based regimens. Methods: Using real-world data from the International Metastatic RCC Database Consortium (IMDC), we conducted a retrospective analysis of patients with advanced ChRCC who received IO-based therapies, including dual IO therapy or IO + VEGF targeted therapy (VEGF-TT), in the first-line setting. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) and ORR. Cox proportional hazards models were used to adjust for age and IMDC risk groups as covariates. A logistic regression was used to determine the association between the odds of achieving a response and RCC subtype. Results: We identified 31 patients with advanced ChRCC and 856 patients with ccRCC treated with IO-based therapies in the first-line setting, with a median age of 61.5 years (IQR: 51.5-69.0). Compared to patients with ccRCC who received IO-based therapies as initial regimens, patients with ChRCC had a lower OS (median OS: 24.7 vs. 50.5 months, respectively; p&lt;0.001) and a lower TTF (median TTF: 4.5 vs. 11.0 months, respectively; p&lt;0.001). Among patients with an evaluable objective response, the ORR was lower among patients with advanced ChRCC, as opposed to those with ccRCC (ORR: 12.0 vs 47.1%, respectively; p&lt;0.001). When evaluating first-line treatment with VEGF-TT monotherapy (sunitinib or pazopanib), no difference in outcomes was found between patients with ChRCC (n=122) and ccRCC (n=6,379) in relation to the primary endpoint of OS, while TTF and ORR suggested better outcomes for ccRCC (Table). Conclusions: In this real-world study, patients with metastatic ChRCC appear to display poor clinical outcomes even with IO-based regimens, as compared to ccRCC. The molecular determinants of poor response require further investigations. [Table: see text]

Treatment responses, outcomes, and prognostic factors associated with them in patients with secondary acute myeloid leukemia

Objective: To evaluate treatment responses, outcomes, and prognostic factors in adults with secondary acute myeloid leukemia (sAML) . Methods: Between January 2008 and February 2021, date of consecutive cases of younger than 65 years of adults with sAML were assessed retrospectively. Clinical characteristics at diagnosis, treatment responses, recurrence, and survival were evaluated. Logistic regression and Cox proportional hazards model were employed to determine significant prognostic indicators for treatment response and survival. Results: 155 patients were recruited, including 38, 46, 57, 14 patients belonging to t-AML, and AML with unexplained cytopenia, post-MDS-AML, and post-MPN-AML, respectively. In the 152 evaluable patients, the rate of MLFS after the initial induction regimen was 47.4%, 57.9%, 54.3%, 40.0%, and 23.1% in the four groups (P=0.076) . The total rate of MLFS after the induction regimen was 63.8%, 73.3%, 69.6%, 58.2%, and 38.5% (P=0.084) , respectively. Multivariate analysis demonstrated that male gender (OR=0.4, 95% CI 0.2-0.9, P=0.038 and OR=0.3, 95% CI 0.1-0.8, P=0.015) , SWOG cytogenetic classification into unfavorable or intermediate (OR=0.1, 95% CI 0.1-0.6, P=0.014 and OR=0.1, 95% CI 0.1-0.3, P=0.004) and receiving low-intensity regimen as induction regimen (OR=0.1, 95% CI 0.1-0.3, P=0.003 and OR=0.1, 95%CI 0.1-0.2, P=0.001) were typical adverse factors impacting the first CR and the final CR; PLT<45 × 10(9)/L (OR=0.4, 95%CI 0.2-0.9, P=0.038) and LDH ≥258 U/L (OR=0.3, 95%CI 0.1-0.7, P=0.005) were independent factors for CR. Among the 94 patients with achieving MLFS, 46 cases had allogeneic hematopoietic stem cell transplantation. With a median follow-up period of 18.6 months, the probabilities of relapse-free survival (RFS) and overall survival (OS) at 3 years were 25.4% and 37.3% in patients with transplantation, and in patients with chemotherapy, the probabilities of RFS and OS at 3-year were 58.2% and 64.3%, respectively. At the time of achieving MLFS, multivariate analysis revealed that age ≥46 years (HR=3.4, 95%CI 1.6-7.2, P=0.002 and HR=2.5, 95%CI 1.1-6.0, P=0.037) , peripheral blasts ≥17.5% at diagnosis (HR=2.5, 95%CI 1.2-4.9, P=0.010 and HR=4.1, 95%CI 1.7-9.7, P=0.002) , monosomal karyotypes (HR=4.9, 95%CI 1.2-19.9, P=0.027 and HR=28.3, 95%CI 4.2-189.5, P=0.001) were typical adverse factors influencing RFS and OS. Furthermore, CR after induction chemotherapy (HR=0.4, 95%CI 0.2-0.8, P=0.015) and transplantation (HR=0.4, 95%CI 0.2-0.9, P=0.028) were substantially linked to longer RFS. Conclusion: Post-MDS-AML and post-MPN-AML had lower response rates and poorer prognoses than t-AML and AML with unexplained cytopenia. In adults with male gender, low platelet count, high LDH, and SWOG cytogenetic classification into unfavorable or intermediate at diagnosis, and receiving low-intensity regimen as the induction regimen predicted a low response rate. Age ≥46 years, a higher proportion of peripheral blasts and monosomal karyotype had a negative effect on the overall outcome. Transplantation and CR after induction chemotherapy were greatly linked to longer RFS.

Use of Intravenous Anakinra for Management of Pediatric Cytokine Storm Syndromes at an Academic Medical Center.

Background: Off-label intravenous (IV) route of anakinra is increasingly recognized to enable higher and faster maximal plasma concentrations than subcutaneous route for treatment of cytokine storm syndromes. Objective: To describe off-label indications of IV anakinra, corresponding dosing and safety profiles, particularly during the coronavirus disease 19 (COVID-19) pandemic. Methods: A retrospective, single-cohort study was conducted at an academic medical center to evaluate use of IV anakinra in hospitalized pediatric patients (age ≤21 years). Institutional Review Board review was considered exempt. The primary endpoint was the primary indication(s) for IV anakinra. The key secondary endpoints were dosing of IV anakinra, previous immunomodulatory therapies, and adverse events. Results: Of 14 pediatric patients, 8 (57.1%) received IV anakinra for treatment of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, whereas 3 and 2 were treated for hemophagocytic lymphohistiocytosis (HLH) and flares of systemic onset juvenile idiopathic arthritis (SoJIA), respectively. The initial dosing regimen of IV anakinra for MIS-C associated with COVID-19 was a median dose of 2.25 mg/kg/dose with a median dosing interval of 12 hours for a median initial treatment duration of 3.5 days. Eleven (78.6%) patients received previous immunomodulatory therapies (IV immune globulin [n = 10; 71.4%] and steroids [n = 9; 64.3%]). No adverse drug events were documented. Conclusion: IV anakinra was used off-label for treatment of MIS-C associated with COVID-19, HLH and SoJIA flares in critically ill patients with no adverse drug events documented. This study helped ascertain the off-label indications of IV anakinra and corresponding patient characteristics.