Two decades (1998 to 2018) of collaborative human immunodeficiency virus clinical pharmacology capacity building in a resource constrained setting.

While important advances have been made in the prevention and treatment of Human Immunodeficiency Virus (HIV) infection, limited expertise and resource constraints to effectively manage rollout of HIV programs often contribute to poor treatment outcomes in Sub-Saharan Africa. In 1998, the University of Zimbabwe (UZ) and the University at Buffalo, State University of New York (UB), developed a collaborative clinical pharmacology capacity building program in Zimbabwe to train the next generation of HIV researchers and support rollout of the national HIV program. The collaboration was funded by research and training grants that were competitively acquired through United States of America government funding mechanisms, between 1998 and 2016. Thirty-eight research fellows were trained and a specialty clinical pharmacology laboratory was established during this period. Knowledge and skills transfer were achieved through faculty and student exchange visits. Scientific dissemination output included sixty-two scholarly publications that influenced three national policies and provided development of guidelines for strategic leadership for an HIV infection-patient adherence support group. The clinical pharmacology capacity building program trained fellows that were subsequently incorporated into the national technical working group at the Ministry of Health and Child Care, who are responsible for optimizing HIV treatment guidelines in Zimbabwe. Despite serious economic challenges, consistent collaboration between UZ and UB strengthened UZ faculty scholarly capacity, retention of HIV clinical research workforce was achieved, and the program made additional contributions toward optimization of antiretroviral therapy in Zimbabwe.

Sources of Variability and Accuracy of Performance Assessment in the Clinical Pharmacology Quality Assurance Proficiency Testing Program for Antiretrovirals.

BACKGROUND: The Clinical Pharmacology Quality Assurance (CPQA) program provides semiannual proficiency testing (PT) of antiretroviral analytes for 11 US and international clinical pharmacology laboratories (CPLs) to ensure interlaboratory comparability. In this article, we provide estimates of the main sources of variability and assess the accuracy of the algorithm for the assessment of performance. METHODS: Descriptive statistics are reported from 13 PT rounds from 2010 to 2016. Eight of the most common antiretroviral analytes were examined. Variance components analysis was used to rank the relative contributions of CPLs, antiretroviral analyte, and concentration category (low, medium, and high) to bias and variability using mixed models. Binary classification metrics of the PT assessment algorithm are calculated in comparison with a model using 95% prediction limits around estimated regression equations. RESULTS: CPLs provided 4109 reported concentrations of 65 unique samples for each of the 8 antiretroviral analytes across 13 PT rounds. Individual CPL accounted for the greatest amount of total variability (4.4%). Individual CPL and analyte combination (interaction) accounted for the greatest amount of bias (8.1%). Analyte alone accounted for 0.5% or less for total variability and bias. Overall, using a ±20% acceptance window around the final target, 97% of individual reported concentrations were scored acceptable, and 96% of antiretroviral/round scores were deemed satisfactory. Comparison with the regression model gave 100% sensitivity but only 34.47% specificity. Narrowing the acceptance window to ±15% improved specificity to 84.47% while maintaining a 99.17% sensitivity. CONCLUSIONS: The current CPQA PT scoring algorithm that use a ±20% acceptance window seems to suffer from a low specificity and may be too lenient. A stricter ±15% acceptance window would increase specificity and overall accuracy while lowering the overall pass rate by only 3%.

Quality assessment for therapeutic drug monitoring in AIDS Clinical Trials Group (ACTG 5146): a multicenter clinical trial.

In a randomized trial, AIDS Clinical Trials Group (ACTG) protocol 5146 (A5146) investigated the use of therapeutic drug monitoring (TDM) to adjust doses of HIV-1 protease inhibitors (PIs) in patients with prior virologic failure on PI-based therapy who were starting a new PI-based regimen. The overall percentage of "PI trough repeats" such as rescheduled visits or redrawn PI trough specimens increased from 2% to 5% to 10% as the process progressed from the clinical sites, the pharmacology specialty laboratory, and the study team, respectively. Cumulatively, this represents a 17% rate of failure to obtain adequate PI trough sample. While targeting a turnaround of 7 days or less from sample receipt to a drug concentration report, 12% of the received specimens required a longer period to report concentrations. The implementation of dosing changes in the TDM arm were achieved within 7 days or less for 56% of the dose change events and within 14 days or less for 77% of dose change events. This quality assurance analysis provides a valuable summary of the specific points in the TDM process that could be improved during a multicenter clinical trial including: 1) shortening the timeline of sample shipment from clinical site to the laboratory; 2) performing the collection of PI trough specimen within the targeted sampling window by careful monitoring of the last dose times and collection times by the clinicians; 3) increasing patient adherence counseling to reduce the number of samples that are redrawn due to suspecting inconsistent adherence; and 4) decreasing the time to successful TDM-based dose adjustment. The application of some of these findings may also be relevant to single-center studies or clinical TDM programs within a hospital.

Simultaneous determination of cortisol, dexamethasone, methylprednisolone, prednisone, prednisolone, mycophenolic acid and mycophenolic acid glucuronide in human plasma utilizing liquid chromatography-tandem mass spectrometry.

Chronic combination immunosuppressive regimens are commonly prescribed to renal transplant recipients. To develop an assay method for pharmacokinetic studies and therapeutic drug monitoring of multiple immunosuppressives, a liquid chromatography-tandem mass spectrometry (LC/MS/MS) approach for the simultaneous analysis of several glucocorticoids, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) was investigated. The resultant method utilized a gradient reverse phase separation over a Symmetry C18 column using an ammonium acetate-methanol mobile phase at pH 3.5. The analytes were detected by coupling the chromatography system via electrospray to a triple quadrupole mass spectrometer. Multiple-reaction monitoring in the negative mode ion (MH-/product) was employed selecting MPA at 319.1/190.9, MPAG at 495.1/191.0, dexamethasone at 391.0/361.0, hydrocortisone at 361.1/331.1, methylprednisolone at 373.1/343.1, prednisone at 357.1/327.2, and prednisolone at 359.1/329.1. The calibration curve concentrations ranged from 3.60 ng/mL to 50 microg/mL with the lowest limit of quantitation for corticosteroids being 3.60-7.20 ng/mL and 0.656-6.75 microg/mL for MPA and MPAG, respectively. The relative standard deviation for quality control intraday variation and interday variation was between 0.76% and 9.57% for all analytes. This assay offers a versatile, unique method for multi-analyte immunosuppressive determinations during combination immunosuppression.