bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Outcomes Following the Use of Archived HIV-1 DNA Sequencing to Guide Antiretroviral Therapy Regimen Adjustment and Simplification
Authors: Ellis Kristen , Nawas George , Chan Connie , York Lawrence , Mar Alexander , Zangeneh Tirdad 
Published: October 2017

Abstract

Background
While favorable new antiretroviral therapy (ART) options are available for HIV disease, the Department of Health and Human Services guidelines recommend against switching suppressive regimens unless there is evidence that the new regimen will be fully active. A new assay analyzes archived HIV pro-viral DNA and can detect resistance mutations when HIV RNA is below the limit of detection, when standard genotyping (GT) is not possible. Small studies have correlated archived DNA GT to historical plasma RNA GT, but there is minimal available data on treatment outcomes when using this assay to determine antiretroviral therapy switch strategies. We evaluated clinical outcomes following ART adjustment based upon results of archived DNA GT testing.

Methods
A retrospective review of electronic medical records was performed at our medical center from October 2014 to October 2016. Inclusion criteria included age ≥ 18 years, archived DNA GT result available, ART changed after archived GT result, and follow up HIV RNA available after ART switch. Data was collected prior to and after ART switching. McNemar’s test was used for categorical variables and paired t-test for continuous variables.

Results
A total of 38 patients were included. Most patients were male (89%), Caucasian (66%), had a history of AIDS diagnosis (45%), had HIV for &gt;10 years (74%), and had baseline ART resistance (24% resistant to 1 class, 37% resistant to ≥ 2 classes). Median baseline CD4 was 532 cells/mm3. At baseline, 31 (82%) patients had HIV RNA &lt; 50 copies/mL. Compared with baseline, 35 (92%) patients were undetectable at furthest follow up (P = 0.22). Median time to furthest follow up was 146.5 days (range 12–485). Overall, 36 (95%) patients had at least one undetectable HIV RNA after switching. None of the patients with an initial undetectable HIV RNA became detectable after switching ART. Average number of pills per day and administrations per day decreased from 3.84 to 1.97 (P &lt; 0.001) and 1.47 to 1.05 (P &lt; 0.001) respectively. The number of patients on protease inhibitors (PIs) decreased from 66% to 21% (P &lt; 0.001).

Conclusion
The use of archived DNA GT to guide ART adjustment may result in maintained viral suppression while allowing for regimens with optimized long-term safety and decreased pill burden.

Disclosures
All authors: No reported disclosures.
The Safety of Substitution of Antiretroviral Regimen in Non-Clinical Trial Settings in Asian Countries
Authors: Jung In Young , Boettiger David , Wong Wingwai , Lee Man Po , Kiertiburanakul Sasisopin , Chaiwarith Romanee , Avihingsanon Anchalee , Tanuma Junko , Kumarasamy N , Kamarulzaman Adeeba , Zhang Fujie , Kantipong Pacharee , Ng Oon Tek , Sim Benedict Lh , Law Matthew , Ross Jeremy , Choi Jun Yong 
Published: October 2017

Abstract

Background
Although substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the safety of substituting antiretroviral regimen in virologically suppressed HIV-infected patients in non-clinical trial settings in Asian countries.

Methods
HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD) were included in this analysis if they started combination antiretroviral therapy (cART) after 2002, were being treated at a center that documented a median rate of viral load (VL) monitoring ≥ 1 tests/patient/year, and experienced a minor or major treatment substitution while on virally suppressive cART (VL &lt; 200 copies/mL). Minor regimen substitutions were defined as within-class changes and major regimen substitutions were defined as changes to a drug class. Virologic failure was defined as having had two viral load measurements &gt; 400 copies/mL. The patterns of substitutions and rate of virologic failure after substitutions were analyzed.

Results
Of 3,994 adults who started ART after 2002, 3,119 (78.1%) had at least one period of virological suppression. Among these, 1,170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of virological failure were 1.48/100person years (95% CI 1.14–1.91) in the minor substitution group and 2.85/100person years (95% CI 1.88–4.33) in the major substitution group, and 2.53/100person years (95% CI 2.20–2.92) among patients that did not undergo a treatment substitution.

Conclusion
The rate of virological failure was relatively low in both major and minor substitution groups, showing that regimen substitution is generally safe in non-clinical trial settings in Asian countries.

Disclosures
All authors: No reported disclosures.
Gender Differences in Virologic Response after Antiretroviral Therapy in Treatment-naïve HIV-infected Individuals: Results from the 550 Clinic HIV Cohort Study.
Authors: Vega Andrea Reyes , Loban Alejandra , Srinivasan Kavitha , Furmanek Stephen , English Connor , Bishop Mary , Spencer Cathy , Truelove Daniel , Ramirez Julio , Raghuram Anupama , Peyrani Paula 
Published: October 2017

Abstract

Background
Controversy still exists regarding gender differences in virologic response between treatment-na•ve HIV-infected individuals. The objective of this study was to evaluate gender difference in virologic and immunologic response to antiretroviral therapy in treatment-na•ve HIV-infected individuals.

Methods
This was a retrospective, observational study of treatment-na•ve HIV-infected individuals managed at the 550 clinic who started antiretroviral therapy (ART) between January 1st, 2010 and December 31, 2015. Patients with available viral load and CD4 counts before and one year after initiating ART were included in this study. Virologic suppression was defined as &lt; 48 HIV-1 RNA copies/mL, and mmunologic recovery was defined as a CD4 count increase of at least 150 cells/mm3. Dichotomous variables were reported in number and percentages and analyzed using Chi-squared tests and Fisher’s exact (whichever was appropriate). Continuous variables were reported as median and interquartile range (IQR) and analyzed using Wilcox rank-sum tests. Multivariate analyses performed were logistic regressions with adjustment for other covariates. P value &lt;0.05 was considered statistically significant. R version 3.3.2 was used for the statistical analysis.

Results
A total of 70 women and 90 men were included in the study. Median age was 41 years (19) for women and 34 years (19) for men (P &lt; 0.001). Virologic suppression was documented in 76% of women and 64% of men (p 0.166). Immune recovery was documented in 60% of women and 68% of men (p 0.323). Multivariate analysis of virologic success is shown in Figure 1 and immunologic recovery is shown in Figure 2.

Conclusion
In our study, gender was not found to be associated with differences in response to ART. As expected, drug abuse continues to be an independent variable associated with lack of virologic suppression. If one of the goals of treatment is to achieve a rapid immunologic response, our study may indicate that regimens containing protease inhibitors should be the ones selected.

Disclosures
All authors: No reported disclosures.
Vancomycin Prescribing Habits – Are We Still Afraid of Mississippi Mud?
Authors: Bulik Catharine C , Bader Justin C , Bhavnani Sujata M , Rubino Christopher M , Sweeney Kim L , Ambrose Paul G , Owens Robert C 
Published: October 2017

Abstract

Background
Debates over the safety and efficacy of vancomycin have plagued clinical practice for more than half a century. A recent paradigm shift has occurred as the science of PK-PD has encouraged the use of optimized regimens which achieve targeted exposures. However, change is slow and we suspect prescribing habits may not be in line with this consensus approach. Herein, using data from electronic decision support software (EDSS), we describe clinicians’ vancomycin prescribing habits.

Methods
Data obtained over a 20-month period from an EDSS included: 1) clinician demographics; 2) patient demographics; 3) clinician-selected antimicrobials; and 4) EDSS suggested PK-PD optimized antimicrobial regimens. A vancomycin regimen was considered to be PK-PD optimized if the EDSS provided percent probability of PK-PD target attainment (PTA) was ≥90%.

Results
Data for 87 clinicians and 104 vancomycin-treated cases were available. Of all clinicians, 62% were clinical pharmacists, 38% were physicians, with close to half of being ID specialists. Of all the clinicians, 55% had ≥10 years of clinical experience. Of the 104 cases, the median (min, max) patient age, weight and creatinine clearance were 43.5 (23, &gt;90) years, 81.6 (47.6, 170.6) kg, and 100.2 (7.3, 188.1) mL/min/1.73 m2, respectively. For 61.5% of selected vancomycin regimens, PTA were ≥90%. The distribution of PTA for the remaining 38.5% of cases is shown in Figure 1. Among these 38.5%, an alternative optimized regimen was presented 97.5% of the time. Further evaluation of clinician demographics among cases with a PK-PD optimized regimen demonstrated that 61% had ≥ 10 years clinical experience while only 44% of those who did not chose a PK-PD-optimized regimen had the same experience. While the majority of clinicians in both the optimized and non-optimized groups were clinical pharmacists, ID physicians represented 55% of all physicians who chose a non-optimized vancomycin regimen.

Conclusion
Data obtained from an EDSS demonstrated that clinicians who chose a non-optimized vancomycin regimen had less experience than those who chose an optimized regimen. Data suggest that education for optimizing vancomycin dosing using PK-PD is needed as part of antimicrobial stewardship training initiatives.

Disclosures
S. M. Bhavnani, ICPD Technologies: Shareholder, stock options. C. M. Rubino, ICPD Technologies: Shareholder, stock options. P. G. Ambrose, ICPD Technologies: Shareholder, stock options.
Vancomycin (VAN) administered as continuous infusion (CIV) vs. intermittent infusion (IIV) in children with Methicillin-Resistant Staphylococcus aureus (MRSA) infections
Authors: Dakhlallah Abe , Adler-Shohet Felice C , Arrieta Antonio , Tran M Tuan 
Published: October 2017

Abstract

Background
Guidelines for treatment of MRSA infections recommend VAN trough (TR) of 15–20 mg/L to achieve a 24-hour ratio of area-under-the-curve (AUC24) over minimum inhibitory concentration (MIC) ≥ 400, the primary pharmacodynamic (PD) parameter that predicts VAN efficacy. However, achieving this target TR in children is difficult in clinical settings and may not be necessary to achieve AUC24/MIC ≥ 400. Additionally, higher doses and TR &gt;15 mg/L have been associated with increased risk for VAN nephrotoxicity. The use of CIV may lead to lower VAN exposure and subsequent toxicity while achieving the desired AUC24/MIC ratio. To our knowledge there are no reports exploring differences in VAN exposure, AUC24/MIC ratio and toxicity between CIV and IIV VAN in children.

Methods
We conducted a retrospective, cohort study between January 1, 2011–December 30, 2016. Children ages 3 months–18 years with an MRSA infection were included. Only the highest VAN level and total daily dose (TDD) within the first 72 hours of treatment were included for analysis. Patients with CrCl &lt; 30 mL/minute/1.73m2 were excluded. Primary outcome was differences in TDD, AUC24 and AUC24/MIC. Secondary outcomes evaluated adverse events.

Results
Twenty-two patients were evaluated, 11 received IIV and 11 received CIV VAN. Median age, weight, gender, baseline serum creatinine, VAN clearance and volume of distribution were similar in both groups. Fewer patients in the IIV group received concomitant nephrotoxic drugs compared with CIV group (5/11 (45%) vs.. 10/11 (91%), P = 0.03). Patients in the IIV group received more VAN (median 85 mg/kg/day vs. 67 mg/kg/day, P = 0.08) and had higher AUC24 (723 mg*hours/L, (IQR 669–752) vs. 572 mg*hours/L, (IQR 459–633), P = 0.02) compared with CIV. Patients in IIV group had lower median TR (16 mg/L vs. 25 mg/L) that required longer time to attain (50.9 hours, (IQR 42–70) vs. 21.5 hours (IQR 17–34), P = 0.04) than serum levels in CIV. Both groups had a median VAN MIC 1 mg/L with a trend towards higher AUC24/MIC observed in IIV group (752 vs. 621, P = 0.07). More patients in IIV group experienced VAN-related adverse events (renal toxicity, infusion reactions, phlebitis) compared with CIV (7/11 (64%) vs. 1/11 (9%), P = 0.01).

Conclusion
In pediatric patients, CIV VAN achieved the recommended PD target in shorter time, and with fewer adverse events compared with IIV.

Disclosures
All authors: No reported disclosures.
Plasma Pharmacokinetics of Ceftolozane/Tazobactam in Pediatric Subjects with Cystic Fibrosis
Authors: Larson Kajal , Bradley John S , Arrieta Antonio , Yang Shan , Yu Brian , Johnson Matthew G , Rizk Matthew , Rhee Elizabeth 
Published: October 2017

Abstract

Background
Ceftolozane/tazobactam (TOL/TAZ), a novel anti-pseudomonal cephalosporin/β-lactamase inhibitor combination, is approved for the treatment of complicated intra-abdominal infections (cIAI) and urinary tract infections (cUTI) in adults. TOL/TAZ has potent activity against Gram-negative pathogens associated with pulmonary infections in cystic fibrosis (CF). Limited data exists on the pharmacokinetics (PK) of TOL/TAZ in the CF population. The aim of this analysis is to evaluate plasma PK parameters in CF and non-CF pediatric subjects to assess whether CF alters the PK of TOL/TAZ.

Methods
Nine subjects with CF were enrolled in the 2 to &lt;18 y old cohort of an ongoing Phase 1 PK study of a single dose of intravenous TOL/TAZ in pediatric subjects with suspected or proven Gram-negative infection (NCT02266706). Population PK models for TOL and TAZ were developed using PK data from 12 adult studies and preliminary PK data from pediatric subjects. An exploratory analysis comparing model-derived plasma TOL and TAZ PK parameters between CF (N = 9) and non-CF (N = 9) pediatric subjects was conducted.

Results
Mean (range) age and weight of the 9 CF subjects were 11.4 y (5.5–17.5 y) and 37.4 kg (17.4–60 kg), respectively. For TOL, the mean (SD) systemic clearance (CL) normalized by weight was 0.16 (0.03) and 0.15 (0.03) L/hours/kg in CF and non-CF subjects, respectively, suggesting no difference in CL; similar observations were made for volume of the central compartment normalized by weight. All subjects achieved the plasma PK/pharmacodynamic (PD) target of %fT&gt;MIC of at least 30% for an MIC of 4 µg/mL.
Differences in weight-normalized CL were more pronounced for TAZ in CF and non-CF subjects (mean [SD]: 0.73 [0.25], 0.42 [0.13] L/hours/kg, respectively). However, the half-life was similar in CF and non-CF subjects (mean [SD]: 0.99 [0.15] hours, 1.08 [0.15] hours, respectively), suggesting that differences are unlikely to be clinically meaningful. At the recommended dose being advanced into Phase 2, subjects are projected to achieve the TAZ plasma PK/PD target of %fT&gt;threshold concentration (Ct) of &gt;20% for a Ct of 1 µg/mL.

Conclusion
Preliminary exploratory analysis of TOL/TAZ PK in a small group of pediatric patients supports evaluation of the same TOL/TAZ dose in children with and without CF in future clinical studies.

Disclosures
K. Larson, Merck: Employee, Salary. S. Yang, Merck: Employee, Salary.; B. Yu, Merck: Employee, Salary. M. G. Johnson, Merck: Employee, Salary. M. Rizk, Merck: Employee, Salary. E. Rhee, Merck: Employee, Salary.
Epidemiology, Outcomes and Prognosis of Central Nervous System Infections in Singapore. Preliminary results from The Singapore Neurologic Infections Programme (SNIP)
Authors: Chan Fu Zi Yvonne , Wijaya Limin , Tan Kevin , Chan Monica , Soon Derek , Ooi Say-Tat , Shafi Humaira , Ei Mon Soe , Ooi Eng Eong , Low Jenny 
Published: October 2017

Abstract

Background
Central Nervous System (CNS) infections frequently result in devastating consequences although the aetiology is seldom definitively identified. To address this knowledge gap, we conducted a prospective study to describe the epidemiology of CNS infections in Singapore.

Methods
Patient enrollment was conducted in 5 adult tertiary hospitals in Singapore, between August 2013 and December 2016. Patients aged ≥16 years who met the inclusion criteria were enrolled. Demographic data, neuroimaging, neurophysiology and biochemical results were collected. Cases were classified as “Confirmed” or “Probable” depending on whether the aetiological agent was detected by either culture or molecular methods in the CSF. The modified Rankin Scale (mRS) was recorded at enrollment, 2 weeks and 6 months, with scores of 0–2 classified as good and 3–6 as poor outcome.

Results
A total of 2061 patients were screened, of whom 199 met the inclusion criteria.
A total of 106 (53.2%), 65 (32.7%) and 28 (14%) cases of meningitis, meningoencephalitis and encephalitis were diagnosed, respectively. An aetiologic agent was identified in 119 (60%) of cases. Mycobacterium tuberculosis (MTb) was the most common cause of meningitis and meningoencephalitis with 23 (13.5%) cases. Herpes simplex virus was the most common aetiology for encephalitis with 3 (10.7%) cases. Immune-mediated aetiologies accounted for 8 (4%) of the total cases. Fatal outcomes were observed in 7 (3.5%) patients.
The absence of focal weakness (aOR 0.024 95% CI 0.001–0.535 P = 0.018) and absence of altered mental status (aOR 0.03; 95% CI 0.002–0.43; P = 0.009) at admission predicted good outcomes at 6 months. Vomiting was associated with poor prognosis (aOR 17.91; 95% CI 1.12–286.04; P = 0.041).

Conclusion
It is surprising that MTb was the most common aetiologic agent although none were fatal. Our study identified aetiologic diagnoses, clinical and biochemical results that correlated with outcome of CNS infections although it also underscores the need for better diagnostic tools for aetiologic confirmation.

Disclosures
All authors: No reported disclosures.
Infectious Causes and Infectious Mimics of Acute Encephalitis: a Prospective Study from Thailand
Authors: Skulsujirapa Benjawan , Wacharapluesadee Supaporn , Petcharat Sininat , Hemachudha Thiravat , Wasontiwong Abhinbhen Saraya , Putcharoen Opass 
Published: October 2017

Abstract

Background
Previous reports of infectious encephalitis in Thailand showed viruses as major pathogens similar to worldwide data. Major viruses in studies varied among Japanese encephalitis, Enteroviruses and Herpesviruses. Infectious etiologies vary by regions, seasons and preventive strategies done. Dynamic change of pathogen is believed to occur continually. Local data in each region is important to develop an algorithm of investigations for the cost-effectiveness.

Methods
This is a prospective study of patients with encephalitis between January 2014 to March 2017 at a tertiary hospital in Bangkok. Microbiological and serological studies were done according to an algorithm based on initial cerebrospinal fluid analysis. Initial tests were for bacteria, fungus, mycobacterium and commonly prevalent viruses. Further tests for infectious etiology were done by stepwise approach if initial tests yielded negative.

Results
Fifty-two patients were enrolled. Twenty-seven (51.9%) patients had no etiology identified. Three patients (5.8%) had bacterial etiology, 10 (19.2%) had viral etiology, and 12 (23%) had immune-mediated encephalitis. Among viral etiologies, VZV was identified in 4 cases, HSV in 3 cases, CMV in 2 cases and measles in 1 case. Baseline characteristic of HIV infection or skin rash was associated with viral infection (p 0.031, p 0.006). Patients with VZV encephalitis might not have active skin lesion. The presence of prodrome, duration of prodrome, neurological onset to peak and physical examination of focal neurodeficit, meningeal irritation signs, and reflex were similar across all etiologies. White blood cell [mean 7.0 (range 0–30) cells/µL] and protein [mean 32.5 (range 11–70.4) mg/dL] from the cerebrospinal fluid of noninfectious etiologies tended to be lower than the levels of infectious causes (p 0.009, p 0.020). All patients survived at 7 days after admission.

Conclusion
A quarter of patients presenting with acute encephalitis in this study had autoimmune and paraneoplastic encephalitis. Infections caused by herpesviruses was the most prevalent viral etiology. Autoimmune and paraneoplastic encephalitis should be kept in the differential diagnosis in patients with acute encephalitis.

Disclosures
S. Wacharapluesadee, USAID: Investigator, Research grant. O. Putcharoen, USAID: Grant Investigator, Research grant.
Development of a Novel Anthrax Vaccine Comprising LF-PA Chimera
Authors: Aggarwal Somya , Somani Vikas , Bhatnagar Rakesh 
Published: October 2017

Abstract

Background
Bacillus anthracis (BA), the etiological agent of anthrax, secretes protective antigen (PA), lethal factor (LF), and edema factor (EF) as major virulence factors. Among them, PA based vaccines are most indispensable for providing immunity against BA, but the low shelf life limits its reliability. Previous studies revealed that PA domain IV includes B-cell epitopes designated as ID I, ID II, and ID III; among them, ID II and ID III have been found to possess more toxin neutralization activity and produce high antibody titre. Moreover, N-terminal region of both LF and EF carries binding site of PA which are homologous to each other. Here, in this study we have developed and evaluate the vaccine efficacy of chimeric vaccine containing ID II-ID III region of PA and N-terminal region of LF and EF (ID-LFn).

Materials and Methods
ID-LFn was generated by overlapping PCR followed by cloning in pET28a. The recombinant protein was then expressed and purified by Ni-NTA chromatography. Reactivity of ID-LFn with anti-PA/LF/EF antibodies was checked by ELISA. Stability was assessed using Circular Dichroism Spectroscopy. The vaccine potential of ID-LFn was evaluated by toxin neutralization assay, lymphocyte proliferation assay, and cytokine analysis. The protection efficacy was analyzed by challenge studies in mice.

Results
ID-LFn was found to be significantly stable as compared with protective antigen. Anti-ID-LFn antibodies recognized PA, LF as well as EF. Though, the total antibody titre, toxin neutralization activity was found to be less than PA but surprisingly, the protection efficacy of ID-LFn was found similar as PA.

Conclusion
The ID-LFn vaccine might be second next generation vaccine showing equal protection but higher shelf life as PA with the capability of neutralizing PA, LF as well as EF at the same time. Thus, it may prove an efficient and reliable treatment strategy against anthrax.

Disclosures
All authors: No reported disclosures.