Companion Drugs Research Articles

HIV-1 resistance and virological failure to treatment with the integrase inhibitors bictegravir, cabotegravir, and dolutegravir: a systematic literature review.

We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.

Pharmacokinetics of extended-release clarithromycin in patients with Mycobacterium ulcerans infection

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC–MS/MS in 30 study participants—20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L—and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

Pan-cancer proteogenomics expands the landscape of therapeutic targets

Fewer than 200 proteins are targeted by cancer drugs approved by the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 cancer types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable proteins reveals a wide abundance range and identifies biological factors that affect mRNA-protein correlation. Integration of proteomic data from tumors and genetic screen data from cell lines identifies protein overexpression- or hyperactivation-driven druggable dependencies, enabling accurate predictions of effective drug targets. Proteogenomic identification of synthetic lethality provides a strategy to target tumor suppressor gene loss. Combining proteogenomic analysis and MHC binding prediction prioritizes mutant KRAS peptides as promising public neoantigens. Computational identification of shared tumor-associated antigens followed by experimental confirmation nominates peptides as immunotherapy targets. These analyses, summarized at https://targets.linkedomics.org, form a comprehensive landscape of protein and peptide targets for companion diagnostics, drug repurposing, and therapy development.

Comparison of Individual Regimen Containing Bedaquiline with Delamanid and Bedaquiline without Delamanid on Efficacy and Safety in Multidrug-resistant Tuberculosis Patients: Implementation in Dr. Soetomo General Academic Hospital, Indonesia.

Bedaquiline is one of the core drugs used to treat multidrug-resistant TB (MDR-TB). Delamanid is one of the companion drugs in group C which is used to complete the treatment regimen when drugs in groups A and B can not be used. This study was conducted to analyze the efficacy and safety between individual regimens containing bedaquiline with delamanid and bedaquiline without delamanid. This was an observational analytic study with a retrospective design in MDR-TB patients treated with individual regimens containing bedaquiline with delamanid (bedaquiline-delamanid group) and bedaquiline without delamanid (bedaquiline group). Efficacy was measured according to the time to Acid Fast Bacilli (AFB) conversion and Mycobacterium tuberculosis culture conversion, while safety was measured specifically on QTc interval prolongation. The median (range) time to AFB conversion in bedaquiline-delamanid group was faster than bedaquiline group, although there was no significant difference (1.5 (1-4) months vs. 1 (1-6) months, P=0.429), the median time to culture conversion in bedaquiline-delamanid group also faster than bedaquiline group, although there was no significant difference (1 (1-6) months vs. 2 (1-6) months, P=0.089). The incidence of QTc interval prolongation in bedaquiline-delamanid group was less than bedaquiline group, although there was no significant difference (26.9% vs. 40.3%, P=0.223). Individual regimens containing bedaquiline with delamanid was proven to provide similar efficacy and safety profiles with individual regimens containing bedaquiline without delamanid. Delamanid should be preferred when selecting drugs to complete the treatment regimen when drugs in groups A and B can not be used.

In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants.

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use of direct-acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study

Key messagesIn this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy.BackgroundThe benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria.MethodsWe included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock.ResultsAmong the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73–1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53–1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71–1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results.ConclusionsInitial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings.

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings.

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study

BackgroundIbrutinib, a first-in-class inhibitor of Bruton’s tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated.MethodsIbrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2.ResultsA total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9–7.5) months in RCC, 4.0 (2.7–4.2) months in GC, and 5.4 (4.1–5.8) months in CRC.ConclusionsClinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours.Trial registrationClinicalTrials.gov, NCT02599324.

A-249 Theranostic Algorithm: sensitivity and Specificity of a Composite Index Test for Guiding Treatment in Severe COVID-19

Abstract Background Since the outbreak of the pandemic, severely affected COVID-19 patients receive standard of care at intensive care unit (ICU), but clinical trials are still ongoing for new expensive treatments. There is a need for guiding therapeutic decisions to restrain the public healthcare costs and to target the most efficient therapy. Based on the pathophysiology of SARS-CoV-2 on its ACE2-receptor, the angiotensin pathway is activated and circulating biomarkers of interest can be measured. This diagnostic test accuracy study describes how to classify COVID-19 patients in severe vs mild cases with the intention of guiding treatment decisions, to prevent long term sequels like pulmonary fibrosis. A theranostic approach is proposed, which combines in vitro diagnostics and personalized therapeutics. Methods N = 17 severely affected COVID-19 with acute respiratory distress syndrome (ARDS) at ICU were included and compared to N = 7 mild or asymptomatic COVID-19 cases and to N = 10 healthy controls. Follow-up samples have been collected during pulmonology consultation at three time points during one year post-ICU (N = 39). Non-parametrical statistics were used; data are expressed as [median (IQR)] and P &amp;lt; 0.05 is considered to be statistically significant. The biological markers angiotensin-(1-7) (Ang-(1-7)), transforming growth factor beta (TGF-β), ferritin, C-reactive protein (CRP from Roche) and Krebs von den Lungen 6 (KL-6 from Fujirebio) were measured in plasma samples. Those biomarkers represent a disequilibrium in lung protection, fibrogenesis, inflammation and hyperplasia of alveolar epithelial cells type II. Cut-off for a composite index was obtained through receiver operating curve (ROC). Results COVID-19 patients show higher Ang-(1-7) concentrations than healthy controls (P &amp;lt; 0.05). Critical patients at ICU show Ang-(1-7) deficit [124 pg/mL (81–154)], compared to asymptomatic COVID-19 cases [147 pg/mL (138–201)] (P &amp;lt; 0.05). COVID-19 patients with insufficient Ang-(1-7) are eligible for substitution therapy and novel expensive therapies beside standard of care, while the subpopulation of high Ang-(1-7) is analyzed with a composite index test including TGF-β, ferritin and CRP. A composite index of &amp;lt;34 differentiates asymptomatic COVID-19 from severe COVID-19 at ICU having acute respiratory distress syndrome (sensitivity = 100%, specificity = 80%, AUC = 0.933, LR = 5). The patients without risk for pulmonary sequels are not eligible for expensive treatment.After 1 year, KL-6 (&amp;lt;275 U/mL) and TGF- β (&amp;lt;34 968 pg/mL) normalise in only 25%, respectively 33% of severe COVID-19 patients. Within the first year of FU post-ICU, the mean KL-6 value in the patient population does not significantly change at different measuring moments (P = 0.63), while TGF-β decreases gradually at 3, 6 and 12 months post-ICU (P &amp;lt; 0.0001). Conclusion This theranostic algorithm predicts whether a patient infected by SARS-CoV-2 is at risk of developing clinical complications and supports clinical decision making concerning therapy. A supported therapeutic choice, based on objective biomarker measurements, could diminish long-term sequelae like pulmonary fibrosis. Clinical trials using companion drugs (e.g. Ang-(1-7) substitution therapy, MAS-receptor agonist), anti-fibrotics, interferon therapy, or monoclonal antibodies, could also rely on those biomarkers. The measurement of Ang-(1-7) for example, could categorize patients in the targeted subpopulation before administrating Ang-(1-7) substitution therapy, aiming at obtaining better treatment efficacy.

Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance.

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-RasG12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-RasG12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.

Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant HIV infection and limited treatment options

Introduction Lenacapavir , the compoundreviewed in this paper, is a novel, potent, and long-acting first-in-classHIV-1 capsid inhibitor that was granted breakthrough therapy designation forHIV treatment by the U.S. Food and Drug Administration in May 2019. Lenacapavirwas subsequently approved, in combination with other antiretroviral agents, forthe treatment of multidrug-resistant HIV in people with HIV who have limitedtreatment options due to safety, intolerance and resistance considerations,based on clinical trial data which demonstrated its efficacy, tolerability, andsafety for that population. Areas Covered This review draws uponpublished and unpublished data of lenacapavir (GS-6207) to discuss itschemistry, mechanism of action, pharmacokinetic and pharmacodynamic properties,as well as efficacy and safety observed in clinical trials; and an expertopinion section discusses its clinical uses, advantages, limitations, andpotential future applications. Expert Opinion Lenacapavir should beused in combination with at least 1 or 2 additional fully active agents, wherepossible, and adherence support is critical for selected companion drugs(particularly if self-administered) to optimize efficacy and preventtreatment-emergent resistance to lenacapavir. Providers should pay attention todrug-drug interactions when initiating lenacapavir.

Metformin Increases Cell Viability and Regulates Pro-Inflammatory Response to Mtb.

Current TB treatment regimens are pathogen-directed and can be severely compromised by the development of drug resistance. Metformin has been proposed as an adjunctive therapy for TB, however relatively little is known about how metformin modulates the cellular interaction between Mtb and macrophages. We aimed to characterize how metformin modulates Mtb growth within macrophages. We utilized live cell tracking through time-lapse microscopy to better understand the biological effect of metformin in response to Mtb infection. Furthermore, the potent first-line anti-TB drug, isoniazid, was used as a comparator and as a companion drug. Metformin caused a 14.2-fold decrease in Mtb growth compared to the untreated control. Metformin combined with isoniazid controlled Mtb growth is slightly better than isoniazid alone. Metformin demonstrated the ability to regulate the cytokine and chemokine response over a 72 hour period, better than isoniazid only. We provide novel evidence that metformin controls mycobacterial growth by increasing host cell viability, and a direct and independent pro-inflammatory response to Mtb. Understanding the impact of metformin on Mtb growth within macrophages will advance our current knowledge on metformin as an adjunctive therapy, providing a new host-directed approach to TB treatment.

Evaluation of integrase resistance in individuals who failed a regimen containing dolutegravir in French and Italian clinical settings.

This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen. Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure. We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5-20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P < 0.001].N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16-0.78), P < 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04-0.23], P < 0.001) were negatively associated with INSTI resistance at failure. In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future.

Abstract 5726: Pan-cancer proteogenomics expands the landscape of therapeutic targets

Abstract Background: Molecularly targeted therapies are critical for improving cancer treatment. Since proteins are the targets of these therapies and functional effectors of genomic aberrations, proteogenomics data from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) provides an unprecedented opportunity to characterize existing and future therapeutic targets for cancer treatment. Approach: CPTAC proteogenomics data from &amp;gt;1000 cancer patients spanning 10 cancer types was used to evaluate current and potential therapeutic targets curated from four databases. Cell line data from DepMap was further integrated to distinguish causations from associations. Computational pipelines were deployed to identify synthetic lethality for targeting tumor suppressor loss and to prioritize tumor associated antigens as immunotherapy targets. Results: We systematically collected 3050 druggable proteins and classified them into 5 tiers to facilitate different applications such as companion diagnostics, drug repurposing, and new therapy development. Many druggable proteins showed poor mRNA-protein correlation, including secreted proteins and proteins whose abundance was correlated with their interaction partners instead of cognate mRNA, highlighting the necessity of direct proteomic quantification of drug targets. 618 druggable proteins showed both overexpression in tumors compared to normal and significant dependency in CRISPR-Cas9 screens of cell lines of the same lineage. Notably, PAK1, a kinase targeted by investigational drugs, demonstrated both overexpression and dependency in all cancer types. A similar analysis of phosphoproteomics data focusing on known activating sites of druggable proteins further revealed targetable dependencies driven by protein hyperactivation. The phosphosite pS50 on PTPN1, a phosphatase targeted by experimental drugs, was increased in 7 cancer types and PTPN1 demonstrated dependency in related cancer cell lines. Based on tumor proteogenomic data and cell line CRISPR-Cas9 screen data, we identified synthetic lethality for difficult to target tumor suppressor losses, revealing TP53 mutations as a candidate biomarker to select breast cancer patients for CHEK1 inhibition, and endometrial cancer patients for treatment with doxorubicin. We identified 140 proteins whose expression was restricted in normal tissues but abnormal in tumors. Experimental analysis of peptides predicted to have high binding affinity to the most common allotype HLA-A02 for 7 prioritized proteins identified 21 peptides from 5 proteins with both strong binding affinity and immunogenicity which could be further investigated as immunotherapy targets. Conclusion: We generate a comprehensive resource of protein and peptide targets that covers multiple therapeutic modalities. This unique resource will pave the way for repurposing of currently available drugs and developing new drugs for cancer treatment. Citation Format: Jonathan T. Lei, Sara R. Savage, Xinpei Yi, Bo Wen, Hongwei Zhao, Lauren K. Somes, Paul W. Shafer, Yongchao Dou, Qiang Gao, Valentina Hoyos, Bing Zhang. Pan-cancer proteogenomics expands the landscape of therapeutic targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5726.

Early efficacy of individual regimens containing bedaquiline in patients with drug resistant tuberculosis

Objective: To evaluate early efficacy of sputum conversion within 6 months of individual regimens containing bedaquiline in patients with drug resistant tuberculosis. Methods: We conducted a retrospective study among patients with drug resistant tuberculosis who were receiving individual regimens containing bedaquiline. The primary outcome was sputum conversion of both smear and culture within 6 months of treatment. We used medical records of drug resistant tuberculosis patients from January 2020 to December 2021. The study was conducted at Dr. Soetomo Hospital, Indonesia from August to October 2022. Results: In this study, 44 eligible drug resistant tuberculosis patients were initiated on regimens containing bedaquiline. There were 52.3% males and the median age was 45.5 years. The rates of previous treatment (70.5%) and lung cavity (36.4%) were high. The most common companion drugs included clofazimine, cycloserine, levofloxacin, and linezolid. Sputum smear and culture conversion was seen in 79.4% and 82.1% at the 2nd month, respectively. More than 97% patients had smear and culture conversion at the end of 6 months. Conclusions: Among drug resistant tuberculosis patients, individual regimens containing bedaquiline were associated with high rates of smear and culture conversion at the end of 6 months. Early efficacy of regimens containing bedaquiline can be used to predict cure rate at the end of treatment.

Efficacy of ceftazidime/avibactam in various combinations for the treatment of experimental osteomyelitis in rabbits caused by OXA-48-/ESBL-producing Escherichia coli.

While the treatment of ESBL-producing Enterobacterales osteomyelitis relies on carbapenems, the optimal regimen for OXA48 types remains unclear. We evaluated the efficacy of ceftazidime/avibactam in different combinations in an experimental model of OXA-48-/ESBL-producing Escherichia coli osteomyelitis. E. coli pACYC184 is a clinical strain harbouring blaOXA-48 and blaCTX-M-15 inserts, with 'increased exposure susceptibility' to imipenem (MIC, 2 mg/L), gentamicin (MIC, 0.5 mg/L), colistin (MIC, 0.25 mg/L), ceftazidime/avibactam (MIC, 0.094 mg/L) and fosfomycin (MIC, 1 mg/L), and resistance to ceftazidime (MIC, 16 mg/L). Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu of OXA-48/ESBL E. coli. Treatment started 14 days later for 7 days in six groups: (1) control, (2) colistin 150.000 IU/kg subcutaneously (SC) q8h, (3) ceftazidime/avibactam 100/25 mg/kg SC q8h, (4) ceftazidime/avibactam + colistin, (5) ceftazidime/avibactam + fosfomycin 150 mg/kg SC q12h, (6) ceftazidime/avibactam + gentamicin 15 mg/kg intramuscularly (IM) q24h. Treatment was evaluated at Day 24 according to bone cultures. In vitro, time-kill curves of ceftazidime/avibactam in combination showed a synergistic effect. In vivo, compared with controls, rabbits treated with colistin alone had similar bone bacterial density (P = 0.50), whereas ceftazidime/avibactam alone or in combinations significantly decreased bone bacterial densities (P = 0.004 and P < 0.0002, respectively). Bone sterilization was achieved using ceftazidime/avibactam in combination with colistin (91%) or fosfomycin (100%) or gentamicin (100%) (P < 0.0001), whereas single therapies were not different from controls. No ceftazidime/avibactam-resistant strains emerged in rabbits treated, regardless of the combination. In our model of E. coli OXA-48/ESBL osteomyelitis, ceftazidime/avibactam in combination was more effective than any single therapy, whatever the companion drug used (gentamicin or colistin or fosfomycin).

Bedaquiline resistance probability to guide treatment decision making for rifampicin-resistant tuberculosis: insights from a qualitative study

BackgroundBedaquiline (BDQ) is a core drug for rifampicin-resistant tuberculosis (RR-TB) treatment. Accurate prediction of a BDQ-resistant phenotype from genomic data is not yet possible. A Bayesian method to predict BDQ resistance probability from next-generation sequencing data has been proposed as an alternative.MethodsWe performed a qualitative study to investigate the decision-making of physicians when facing different levels of BDQ resistance probability. Fourteen semi-structured interviews were conducted with physicians experienced in treating RR-TB, sampled purposefully from eight countries with varying income levels and burden of RR-TB. Five simulated patient scenarios were used as a trigger for discussion. Factors influencing the decision of physicians to prescribe BDQ at macro-, meso- and micro levels were explored using thematic analysis.ResultsThe perception and interpretation of BDQ resistance probability values varied widely between physicians. The limited availability of other RR-TB drugs and the high cost of BDQ hindered physicians from altering the BDQ-containing regimen and incorporating BDQ resistance probability in their decision-making. The little experience with BDQ susceptibility testing and whole-genome sequencing results, and the discordance between phenotypic susceptibility and resistance probability were other barriers for physicians to interpret the resistance probability estimates. Especially for BDQ resistance probabilities between 25% and 70%, physicians interpreted the resistance probability value dynamically, and other factors such as clinical and bacteriological treatment response, history of exposure to BDQ, and resistance profile were often considered more important than the BDQ probability value for the decision to continue or stop BDQ. In this grey zone, some physicians opted to continue BDQ but added other drugs to strengthen the regimen.ConclusionsThis study highlights the complexity of physicians' decision-making regarding the use of BDQ in RR-TB regimens for different levels of BDQ resistance probability.. Ensuring sufficient access to BDQ and companion drugs, improving knowledge of the genotype–phenotype association for BDQ resistance, availability of a rapid molecular test, building next-generation sequencing capacity, and developing a clinical decision support system incorporating BDQ resistance probability will all be essential to facilitate the implementation of BDQ resistance probability in personalizing treatment for patients with RR-TB.

In vitro prediction of the lower/upper-critical biofluid flow choking index and in vivo demonstration of flow choking in the stenosis artery of the animal with air embolism

<i>In vitro</i> prediction of the lower/upper-critical biofluid flow choking index and <i>in vivo</i> demonstration of flow choking in the stenosis artery of the animal with air embolism

Programmatic management of rifampicin-resistant tuberculosis with standard regimen in Cameroon: a retrospective cohort study

ObjectivesTo describe treatment outcomes for rifampicin-resistant tuberculosis (Rr-TB) started on standard regimen and the frequency of acquired drug resistance in patients treated using the standard treatment regimen (STR) in Cameroon between 2015-2019. MethodsThis is a retrospective cohort study. Rr-TB patients were initiated on the STR, including a fluoroquinolone (FQ), a second-line injectable drug (SLI), and companion drugs. In case of resistance to fluoroquinolones (FQr) at baseline, FQ, SLI and ethionamide were replaced by bedaquiline, delamanid, and linezolid in a modified treatment regimen (mTR), FQr-mTR. In case of resistance to SLI (SLIr) at baseline, SLI was replaced by linezolid (LZD), SLIr-mTR. Logistic regression and competing risk regression were used to estimate predictors of early (first eight weeks) mortality and overall mortality, respectively. ResultsOf 709 patients started on a standard regimen, treatment success occurred in 84.7% (587/693), 72.7% (8/11) and 100% (10/10) of patients treated with STR, FQr-mTR and SLIr-mTR as final regimens, respectively. Three (0.6%) patients acquired FQr during treatment. Early mortality occurred in 4.1% (29/709) and was associated with being HIV positive, male sex and being underweight. Overall mortality was associated with missing drug-susceptibility testing results at baseline, being HIV positive, age>40 and male sex. ConclusionProgrammatic management of Rr-TB, with additional second-line drug resistance treated with mTR, resulted in excellent treatment outcomes.

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue.

Artemisinin, isolated from the traditional Chinese medicinal plant qīng hāo 青蒿 (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gōng téng 雷公藤 (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50–0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55–0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.