Pharmacokinetics of apixaban in patients undergoing pancreaticoduodenectomy (PAP-UP).

OBJECTIVE: The impact of pancreaticoduodenectomy on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who had previously undergone pancreaticoduodenectomy. MATERIALS AND METHODS: A single 10-mg dose of apixaban was administered to 4 volunteers who underwent pancreaticoduodenectomy at least 6 months prior. The maximum plasma apixaban concentration (Cmax) and area under the plasma concentration time-curve (AUC0-24, AUC0-inf) were compared against healthy historical control subjects (N = 12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence. RESULTS: In pancreaticoduodenectomy patients, AUC0-24 and AUC0-inf were 1,861 and 2,080 ng×h/mL, respectively. The GMRs of AUC0-24 and AUC0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88 - 1.83) and 1.18 (90% CI 0.82 - 1.72). The mean Cmax of apixaban was 201 ng/mL (SD 15.6) occurring at a median tmax of 3.25 hours (range 2.5 - 4 hours). The GMR of Cmax between study subjects and healthy controls was 1.12 (90% CI 0.77 - 1.63). CONCLUSION: The pharmacokinetic characteristics of apixaban in subjects who had undergone pancreaticoduodenectomy are not significantly different from those of healthy controls. Though the sample size of this study is small, results suggest that no change to apixaban dose regimen is needed in patients who have had a pancreaticoduodenectomy.

Association between surgical quality and long-term survival in lung cancer.

OBJECTIVES: There are significant variations in both perioperative and long-term outcomes after lung cancer resection. While perioperative outcomes are often used as comparative measures of quality, they are unreliable, and their association with long-term outcomes remain unclear. In this context, we evaluated whether historical perioperative mortality after lung cancer resection is associated with 5-year survival. PATIENTS AND METHODS: The National Cancer Database (NCDB) was queried to identify patients diagnosed with non-small cell lung cancer (NSCLC) in 2010-2016 who underwent surgical resection (n = 234200). Hospital-level reliability-adjusted 90-day mortality rate quartiles for 2010-2013 was used as the independent variable to analyze 5-year survival for patients diagnosed in 2014-2016 (n = 85396). RESULTS: There were 85,396 patients in the 2014-2016 cohort across 1,086 hospitals. Overall observed 90-day mortality rate was 3.2% (SD 17.6%) with 2.6% (SD 16.0%) for the historically best performing quartile vs. 3.9% (SD 19.4%) for the worst performing quartile (p < 0.0001). Patients who underwent resection at hospitals with the best historical mortality rate had significantly better 5-year survival across all stages compared to those treated at hospitals in the worst performing quartile in multivariate Cox regression analysis (all stages - HR 1.21 [95% CI 1.15-1.26]; stage I - HR 1.19 [95% CI 1.12-1.25]; stage II - HR 1.20 [95% CI 1.09-1.32]; stage III - HR 1.36 [95% CI 1.20-1.54]) and Kaplan-Meier survival estimates (all stages - p < 0.0001, stage I - p < 0.0001; stage II - p = 0.0004; stage III - p < 0.0001). CONCLUSION: With expanded lung cancer screening criteria and likely increase in early-stage detection, profiling performance is paramount to ensuring mortality benefits. We found that episodes surrounding surgical resection may be used to profile long-term outcomes that likely reflect quality across a broader context of care. Evaluating lung cancer care quality using perioperative outcomes may be useful in profiling provider performance and guiding value-based payment policies.

In Situ Raman Methodology for Online Analysis of CO2 and H2O Loadings in a Water-Lean Solvent for CO2 Capture.

Carbon capture represents a key pathway to meeting climate change mitigation goals. Powerful next-generation solvent-based capture processes are under development by many researchers, but optimization and testing would be significantly aided by integrating in situ monitoring capability. Further, real-time water analysis in water-lean solvents offers the potential to maintain their water balance in operation. To explore data acquisition techniques in depth for this purpose, Raman spectra of CO2, H2O, and a single-component water-lean solvent, N-(2-ethoxyethyl)-3-morpholinopropan-1-amine (2-EEMPA) were collected at different CO2 and H2O concentrations using an in situ Raman cell. The quantification of CO2 and H2O loadings in 2-EEMPA was done by principal component regression and partial least squares methods with analysis of uncertainties. We conclude with discussions on how this simultaneous online analysis method to quantify CO2 and H2O loadings can be an important tool to enable the optimal efficiency of water-lean CO2 solvents while also maintaining the critical water balance under operating conditions relevant to post-combustion CO2 capture.

Robotic Parenchymal-Sparing Pancreatectomy: A Systematic Review.

BACKGROUND: Parenchymal-sparing approaches to pancreatectomy are technically challenging procedures but allow for preserving a normal pancreas and decreasing the rate of postoperative pancreatic insufficiency. The robotic platform is increasingly being used for these procedures. We sought to evaluate robotic parenchymal-sparing pancreatectomy and assess its complication profile and efficacy. METHODS: This systematic review consisted of all studies on robotic parenchymal-sparing pancreatectomy (central pancreatectomy, duodenum-preserving partial pancreatic head resection, enucleation, and uncinate resection) published between January 2001 and December 2022 in PubMed and Embase. RESULTS: A total of 23 studies were included in this review (n = 788). Robotic parenchymal-sparing pancreatectomy is being performed worldwide for benign or indolent pancreatic lesions. When compared to the open approach, robotic parenchymal-sparing pancreatectomies led to a longer average operative time, shorter length of stay, and higher estimated intraoperative blood loss. Postoperative pancreatic fistula is common, but severe complications requiring intervention are exceedingly rare. Long-term complications such as endocrine and exocrine insufficiency are nearly nonexistent. CONCLUSIONS: Robotic parenchymal-sparing pancreatectomy appears to have a higher risk of postoperative pancreatic fistula but is rarely associated with severe or long-term complications. Careful patient selection is required to maximize benefits and minimize morbidity.

Salvage endoscopic ultrasound-guided gastrojejunostomy as a bridge to definitive surgical therapy for duodenal adenocarcinoma presenting with duodenal stent obstruction.

The utilization of endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) in the setting of an obstructed (ingrown) duodenal stent as a bridge to pancreaticoduodenectomy (PD) remains undescribed. Herein, we report a case study of a 51-year-old patient who underwent EUS-GJ using lumen apposing metal stent (LAMS) for an obstructed duodenal stent during neoadjuvant treatment for duodenal adenocarcinoma. The patient ultimately underwent surgical resection by a classic PD 14 weeks after LAMS placement. EUS-GJ using LAMS represents a potential option as a salvage bridge to surgery for duodenal obstruction in the setting of an obstructed duodenal stent.

Surgical Outcomes in the National Lung Screening Trial Compared With Contemporary Practice.

BACKGROUND: The National Lung Screening Trial (NLST) established a role for lung cancer screening. Mortality benefits with screening are predicated on successful treatment with low surgical mortality. Given variations observed in perioperative outcomes after lung cancer resection, it remains unknown whether benefits observed in the NLST are generalizable to a broader population. We sought to determine whether NLST perioperative outcomes are reflective of contemporary practice in a national cohort. METHODS: We identified patients diagnosed with non-small cell lung cancer who underwent lung resection in the 2014 to 2015 National Cancer Database (NCDB) and the NLST. We compared demographic and cancer characteristics in both datasets. We used hierarchical logistic regression to compare 30-day and 90-day postoperative mortality across facilities in both datasets. RESULTS: In all, 65054 patients in NCDB and 1003 patients in the NLST treated across 1119 NCDB hospitals and 33 NLST hospitals were included. After risk and reliability adjustment, mean 30-day and 90-day mortality were significantly higher among NCDB hospitals (mean 30-day, 2.2 [95% confidence interval (CI), 2.2 to 2.2] vs 1.8 [95% CI, 1.8 to 1.8], P < .001; mean 90-day, 4.2 [95% CI, 4.2 to 4.3] vs 2.9 [95% CI, 2.9 to 2.9], P < .001). Variation in risk- and reliability-adjusted 30-day mortality (95% CI, 1.1% to 4.9%) and 90-day mortality (95% CI, 2.6% to 9.7%) was observed among NCDB hospitals. Adjusted mortality was similar among NLST facilities (30 days, 1.8% to 1.8%; 90 days, 2.9% to 2.9%). CONCLUSIONS: Risk- and reliability-adjusted postoperative mortality varies widely in a national cohort compared with outcomes observed in the NLST. Efforts to minimize this variation are needed to ensure that benefits of lung cancer screening are fully realized in the United States.

Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma.

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

Outcomes in Lung Cancer Surgery: Capturing Reliable Metrics.

BACKGROUND: Measuring variation in perioperative outcomes to accurately discriminate performance between surgical providers may be limited by reliability. We aimed to evaluate reliability estimates of metrics associated with lung cancer resection. METHODS: We performed a retrospective cohort study utilizing the 2015 National Cancer Database to identify patients undergoing lung cancer resection. Primary outcomes were reliability estimates for perioperative outcomes and for measures of adherence to clinical benchmarks, generated through hierarchical multilevel modeling techniques. RESULTS: We identified 27,300 patients undergoing resection. Overall risk-adjusted and reliability-adjusted 30-day and 90-day mortality rates were 1.7% and 3.3%, respectively; 61.0% and 41.1% of eligible patients received stage-appropriate adjuvant and neoadjuvant therapy. Video-assisted thoracoscopic surgery was performed in 59.6% of cases with clinical stage I disease. The mean reliability of 30-day and 90-day mortality was 0.11 ± 0.09 and 0.22 ± 0.15, respectively; for performing video-assisted thoracoscopic surgery for stage I disease, reliability was 0.97 ± 0.04. When stratified by hospital volume quartile, the mean reliability of 30-day mortality was 0.04 ± 0.03 in the lowest quartile and 0.20 ± 0.10 in the highest quartile. Only 14% of hospitals met an established 0.7 reliability benchmark for 30-day and 90-day mortality, but over 97% of hospitals exceeded these benchmarks for providing stage-appropriate systemic therapy and performing VATS for stage I disease. CONCLUSIONS: Metrics used to compare lung cancer surgical performance between providers have varying levels of reliability. Reliability should be considered when profiling providers, which will become particularly important as lung cancer treatment under screening programs continues to expand.

Splenic-vasculature involvement is associated with poor prognosis in resected distal pancreatic cancer.

BACKGROUND: Distal pancreatic carcinoma is one of the most lethal cancers largely due to its high incidence of distant metastasis. This study aims to assess the prognostic value of splenic-vasculature involvement in resected distal pancreatic carcinoma. METHODS: In this retrospective study, we collected the clinicopathologic information of 454 patients with pancreatic cancer and performed univariate and multivariate analyses to identify factors associated with progression-free survival (PFS) and overall survival (OS), with an emphasis on the prognostic value of splenic-artery and -vein involvement. RESULTS: Univariate analysis revealed that larger tumor size, non-intraductal papillary mucinous neoplasm (non-IPMN)-associated adenocarcinoma, poor differentiation, stage pT3, nodal metastasis, lymphovascular invasion, perineural invasion, and pathologic and radiographic evidence of splenic-vein invasion were significantly associated with shorter PFS and OS (all P < 0.05). Multivariate analysis confirmed non-IPMN-associated adenocarcinoma, stage pT3, stage pN1-2, and post-operative adjuvant chemotherapy as independent risk factors for both PFS and OS, and larger tumor size and radiographic evidence of splenic-artery invasion as predictors of PFS only. CONCLUSION: Guidelines should be developed for a uniform approach with regard to the examination and reporting of the status of the splenic vasculature when dealing with distal-pancreatic-cancer specimens.

Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival.

BACKGROUND: The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown. METHODS: We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival. RESULTS: Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5-0.7). CONCLUSIONS: Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.

Is the placement of jejunostomy tubes in patients with esophageal cancer undergoing esophagectomy associated with increased inpatient healthcare utilization? An analysis of the National Readmissions Database.

BACKGROUND: Patients undergoing esophagectomy often receive jejunostomy tubes (j-tubes) for nutritional supplementation. We hypothesized that j-tubes are associated with increased post-esophagectomy readmissions. STUDY DESIGN: We identified esophagectomies for malignancy with (EWJ) or without (EWOJ) j-tubes using the 2010-2015 Nationwide Readmissions Database. Outcomes include readmission, inpatient mortality, and complications. Outcomes were compared before and after propensity score matching (PSM). RESULTS: Of 22,429 patients undergoing esophagectomy, 16,829 (75.0%) received j-tubes. Patients were similar in age and gender but EWJ were more likely to receive chemotherapy (24.2% vs. 15.1%, p < 0.01). EWJ was associated with decreased 180-day inpatient mortality (HR 0.72 [0.52-0.99]) but not with higher readmissions at 30- (15.2% vs. 14.0%, p = 0.16; HR 0.9 [0.77-1.05]) or 180 days (25.2% vs. 24.3%, p = 0.37; HR 0.94 [0.79-1.10]) or increased complications (p = 0.37). These results were confirmed in the PSM cohort. CONCLUSION: J-tubes placed in the setting of esophagectomy do not increase inpatient readmissions or mortality.

Is the Use of Intraoperative Frozen Section During Pancreaticoduodenectomy Justified?

BACKGROUND: Intraoperative frozen section (IFS) is routinely utilized by many surgeons during pancreaticoduodenectomy. However, its utility has not been rigorously studied. METHODS: Patients who underwent pancreaticoduodenectomy between 2006 and 2015 were identified from institutional data. Measures of diagnostic accuracy of frozen section and multivariate logistic regression are reported. RESULTS: The cohort included 1076 patients. Of resected specimens, 73.3% were malignant. IFS and final pathologic review (the gold standard) were discrepant for (1) pathologic diagnosis or (2) resection margin status in 5.3% and 3.3% of cases. The sensitivity, specificity, and accuracy of IFS for histologic determination of malignancy were 97.2%, 95.3%, and 96.7% respectively. For resection margins, they were 92.3%, 99.3%, and 96.8%, respectively. Positive bile duct and neck margins were revised intraoperatively 62% and 65% of the time, respectively; positive uncinate margins were never resected but led surgeons to avoid revision of a second positive margin in 13% of cases (4.2% of all PDA). Operative changes were rarely noted in the presence of benign disease (n = 11, 1.0%); conversion to total pancreatectomy based on positive margins was performed in just 13 cases (1.2%). Upon multivariable analysis, a positive neck margin proved to be the greatest predictor for a revised resection margin (AOR 16.9 [4.8-59.8]), whereas a positive uncinate margin or a diagnosis of chronic pancreatitis was protective against IFS-driven operative changes (AOR 0.25 [0.09-0.73]; AOR 0.16 [0.13-0.19]). CONCLUSIONS: IFS is highly accurate and guides reresection of margins. However, selective omission of IFS may be justified for cases where benign disease is suspected.

Finding the Most Favorable Timing for Cholecystectomy after Percutaneous Cholecystostomy Tube Placement: An Analysis of Institutional and National Data.

BACKGROUND: Early cholecystectomy (E-CCY; 8 weeks or less) after percutaneous cholecystostomy tube (PCT) placement has been associated with increased postoperative complications, but this finding has not been validated at a national level and PCT-related complications and interventions (PCT-RCIs) were not evaluated. STUDY DESIGN: Adults with PCT for acute cholecystitis subsequently undergoing CCY were identified within the Nationwide Readmission Database (2010-2015) and our institution (2017-2019). Adjusted relative risks (aRRs) of postoperative complications were estimated using Poisson regression comparing E-CCY with delayed cholecystectomy (D-CCY; more than 8 weeks) within the nationwide cohort. Institutional PCT-RCIs, operative data, and postoperative outcomes were compared between E-CCY and D-CCY using chi-square and Kruskal-Wallis tests. RESULTS: Of 6,145 patients from the Nationwide Readmission Database, 32.9% were D-CCY. Risk-adjusted analysis identified no differences between E-CCY and D-CCY in complications (aRR 0.98; 95% CI, 0.89 to 1.07), mortality (aRR 0.88; 95% CI, 0.43 to 1.81), or 30-day readmissions (aRR 1.04; 95% CI, 0.85 to 1.27). Risk-adjusted analyses assessing the association of time to interval cholecystectomy (IC) with morbidity indicated an increased risk of surgical complications in the first month after PCT placement (aRR 1.17; 95% CI, 1.08 to 1.33). In the institutional cohort (E-CCY, n = 23; D-CCY, n = 45), there were no statistically significant differences found in estimated blood loss, length of stay, and postoperative complications. There were increased PCT-RCIs in the D-CCY group (26.9% E-CCY vs 69% D-CCY; p < 0.01) based on our unadjusted analysis. CONCLUSIONS: Increased operative complications when IC is performed within 1 month of PCT placement and increased PCT-RCIs when IC is performed 8 weeks after PCT placement suggest that the most favorable timing for IC is between 4 and 8 weeks after PCT placement.

A 10-year ACS-NSQIP Analysis of Trends in Esophagectomy Practices.

BACKGROUND: Esophagectomy practices have evolved over time in response to new technologies and refinements in technique. Using the National Safety and Quality Improvement Program (NSQIP) database, we aimed to describe trends for esophagectomy in terms of approach, surgeon specialty, and associated outcomes. MATERIALS AND METHODS: Adult patients undergoing esophagectomy were identified within the 2007-2017 NSQIP database. The proportion of cases performed using different approaches was trended over time. Outcomes were compared with chi-squared and t-tests. Multivariate logistic regression was used to identify factors associated with outcomes and provide risk-adjusted measures. RESULTS: A total of 10,383 esophagectomies were included; 6347 (61.1%) were performed for cancer. The proportion of esophagectomies performed via the Ivor Lewis approach (ILE) increased between 2007 (37.0%) and 2017 (62.4%). Simultaneously, transhiatal esophagectomies (THEs) decreased from 41.1% to 21.5% (P < 0.001). THE was more frequently performed in patients with higher baseline probability of mortality (2.3% versus 2.0%, P < 0.001) and morbidity (32.2% versus. 28.7%, P < 0.001). The percentage performed with cardiothoracic surgeons increased from 0.8% in 2007 to 50.3% in 2017 (P < 0.001). The risk-adjusted complication rate was 45% for THE, 40% for ILE, and 50% for McKeown (MCK) esophagectomy (P < 0.001). The risk-adjusted rate of surgical site infection was 17.3% for THE, 13.1% for ILE, and 19% for MCK (P = 0.001). Within risk-adjusted analysis, surgical approach was not associated with complications. CONCLUSIONS: ILE has emerged as the predominant approach for esophagectomy nationwide among NSQIP-participating institutions and may be associated with lower complication rates than THE. The use of MCK esophagectomy has remained stable but is associated with increased complications.

Validation of American Joint Committee on Cancer 8th edition of TNM staging in resected distal pancreatic cancer.

BACKGROUND: In order to improve risk stratification and clinical management of the pancreatic ductal adenocarcinoma (PDAC), the American Joint Committee on Cancer (AJCC) has published its eighth edition staging manual. Some major changes have been introduced in the new staging system for both T and N categories. Given the rarity of resectable disease, distal pancreatic cancer is likely underrepresented in the published clinical studies, and how the impact of the staging system actually reflects on to clinical outcomes remain unclear. AIM: To validate the AJCC 8th edition of TNM staging in distal PDAC. METHODS: A retrospective cohort study was performed in seven academic medical centers in the United States. Clinicopathological prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated through univariate and multivariate analyses. RESULTS: Overall, 454 patients were enrolled in the study, and were divided into 2 subgroups: Invasive intraductal papillary mucinous neoplasms (IPMN) (115 cases) and non-IPMN associated adenocarcinoma (339 cases). Compared to invasive IPMN, non-IPMN associated adenocarcinomas are more common in relatively younger patients, have larger tumor size, are more likely to have positive lymph nodes, and are associated with a higher tumor (T) stage and nodal (N) stage, lymphovascular invasion, perineural invasion, tumor recurrence, and a worse PFS and OS. The cohort was predominantly categorized as stage 3 per AJCC 7th edition staging manual, and it's more evenly distributed based on 8th edition staging manual. T and N staging of both 7th and 8th edition sufficiently stratify PFS and OS in the entire cohort, although dividing into N1 and N2 according to the 8th edition does not show additional stratification. For PDAC arising in IPMN, T staging of the 7th edition and N1/N2 staging of the 8th edition appear to further stratify PFS and OS. For PDAC without an IPMN component, T staging from both versions fails to stratify PFS and OS. CONCLUSION: The AJCC 8th edition TNM staging system provides even distribution for the T staging, however, it does not provide better risk stratification than previous staging system for distal pancreatic cancer.

Twice-Daily Doravirine Overcomes the Interaction Effect from Once-Weekly Rifapentine and Isoniazid in Healthy Volunteers.

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC0-12 ) and C12 in the presence of RPT + INH compared with DOR alone were 0.71 (0.60-0.85) and 0.69 (0.54-0.89), respectively. Although exposures were moderately reduced in the presence of RPT + INH, trough DOR values were within the concentration range associated with virological suppression. These results demonstrate that a modest decrease in DOR exposure would unlikely be clinically relevant in a virally suppressed patient co-administered once-weekly RPT + INH.