Tenofovir diphosphate in dried blood spots and HIV-1 resistance in South Africa.

BACKGROUND: Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA. METHODS: Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median [IQR] TFV-DP by genotype outcome. RESULTS: Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 [4;7] months on study, and a median EA of 33.3 [13.3;53.3]%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 [3.2;4.5] log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 [227-661] fmol/punch, p = 0.035; EA 45 [24.9; 59.2]%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 [150-247] fmol/punch, EA 20 [6.7;36.7]%) and in individuals who did not have resistance (n = 3, 39.9 [16.6; 93.9] fmol/punch; EA 33.3 [16-38]%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H). CONCLUSION: TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance.

Measuring ART Adherence Among Young Adults with Perinatally Acquired HIV: Comparison Between Self-report, Telephone-Based Pill Count, and Objective Pharmacologic Measures.

Tenofovir diphosphate (TVF-DP) can be quantified in red blood cells (RBCs) and dried blood spots (DBS) and can objectively measure ART adherence and predict viral suppression. Data on the association of TFV-DP with viral load are very limited in adolescents and young adults (AYA) living with perinatally-acquired HIV (PHIV), as are data comparing TFV-DP to other measures of ART adherence, such as self-report and unannounced telephone pill count. Viral load and ART adherence (self-report, TFV-DP and unannounced telephone pill count) were assessed and compared among 61 AYAPHIV recruited from an ongoing longitudinal study (CASAH) in New York City.

A practical method to measure GFR in people with type 1 diabetes.

AIMS: Improved early diagnostic methods are needed to identify risk for kidney disease in people with type 1 diabetes. We hypothesized that glomerular filtration rate (GFR) measured by iohexol clearance in dried blood spots (DBS) on filter paper would be comparable to plasma (gold-standard) and superior to estimated GFR (eGFR) and, second, that adjustment for ambient blood glucose would improve accuracy and precision of GFR measurement. METHODS: GFR was measured by iohexol clearance in plasma, DBS, and as estimated by the CKD-Epidemiology Collaboration equations in 15 adults with type 1 diabetes at two visits, one euglycemic and one hyperglycemic. RESULTS: GFR measured by DBS was more comparable and less biased than GFR cystatin C, serum creatinine, and both combined. GFR was higher during hyperglycemia. Correction for between visit glycemia statistically significantly reduced bias and mean squared error for GFR measured by DBS as compared to gold-standard during euglycemia. CONCLUSIONS: Iohexol clearance measured with DBS performed better than eGFR methods. Correction for ambient blood glucose improved precision and accuracy of GFR measurement. This method is more convenient than the gold-standard GFR method and may improve screening and diagnostic capabilities in people with type 1 diabetes, especially when GFR is >60ml/min/1.73m(2).

The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients.

We determined the effects of lopinavir/ritonavir on tenofovir renal clearance. Human immunodeficiency virus-infected subjects taking tenofovir disoproxil fumarate (TDF) were matched on age, race, and gender and were enrolled into one of the following two groups: group 1: subjects taking TDF plus lopinavir/ritonavir plus other nucleoside reverse transcriptase inhibitors (NRTIs); group 2: subjects taking TDF plus NRTIs and/or non-NRTIs but no protease inhibitors. Twenty-four-hour blood and urine collections were carried out in subjects for tenofovir quantification. Drug transporter genotype associations with tenofovir pharmacokinetics were examined. In 30 subjects, median (range) tenofovir apparent oral clearance, renal clearance, and fraction excreted in urine were 34.6 l/h (20.6-89.5), 11.3 l/h (6.2-22.6), and 0.33 (0.23-0.5), respectively. After adjusting for renal function, tenofovir renal clearance was 17.5% slower (P=0.04) in subjects taking lopinavir/ritonavir versus those not taking a protease inhibitor, consistent with a renal interaction between these drugs. Future studies should clarify the exact mechanism and whether there is an increased risk of nephrotoxicity.

Virtual reality: using the virtual world to improve quality of life in the real world.

Mental health professionals are increasingly integrating advances in technology to improve the health of those in their care (American Psychological Association, 2000). The authors describe the immersive properties of virtual reality and its importance for clinical purposes and then review the literature describing current clinical applications of virtual reality (VR) and research documenting its efficacy. Virtual reality has been used in the treatment of specific phobias, posttraumatic stress disorder, eating disorders, and pain management.

Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir.

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

Early case reports of dyslexia in the United States and Europe.

Current understanding of reading disabilities is rooted in the early observations of physicians dating as far back in history as the 17th century. This article reviews medical case study research from the United Kingdom, Germany, and the United States that identified characteristics, etiological factors, and treatment methods of reading disorders. The physicians involved provided rich descriptions of the personal struggles of individuals who lost the ability to read because of brain insult as well as of those who failed to achieve literacy because of reading disability. Although many of the theories that were advanced by these early researchers have not been supported by current investigations, others have been substantiated and withstand the test of time. This article also addresses the validity of case study research from an historic and current-day perspective.

Indinavir plasma protein binding in HIV-1-infected adults.

OBJECTIVE: To quantify unbound indinavir concentrations and characterize indinavir plasma protein binding in HIV-infected adults. DESIGN: Pharmacokinetic study in antiretroviral-naive, HIV-infected persons with CD4 T lymphocytes > 100 x 10(6) cells/L and HIV-RNA in plasma >5000 copies/ml at baseline who were participating in an open-label study of zidovudine, lamivudine and indinavir therapy. METHODS: Eight men underwent 8 h intensive pharmacokinetic studies for indinavir on two occasions 6 months apart. Unbound indinavir was separated by ultra-filtration, and unbound and total concentrations were quantified by a validated high-performance liquid chromatography method. RESULTS: Overall indinavir protein binding was 61+/-6%, with a range among the profiles of 54 to 70%. Indinavir binding was higher at the 8 h post-dose concentration compared with the 1 h post-dose concentration (66 versus 57%, P = 0.0006). CONCLUSIONS: The mean 61% protein binding for indinavir in these HIV-infected persons is similar to the in vitro report of 60%. However, the fraction bound was concentration-dependent, and considerable variability in binding was present among patients. Quantification of unbound protease inhibitor concentrations opens new avenues of research to advance our understanding of the pharmacologically-relevant moieties of antiretroviral agents and thereby the pharmacotherapy of HIV infection.

Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons.

OBJECTIVE: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. DESIGN: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. METHODS: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. RESULTS: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. CONCLUSION: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.

Semen and serum pharmacokinetics of zidovudine and zidovudine-glucuronide in men with HIV-1 infection.

STUDY OBJECTIVE: To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1). DESIGN: Open-label observational study. SETTING: University-affiliated teaching hospital and research center. PATIENTS: Four asymptomatic HIV-1-infected men. INTERVENTIONS: Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously. MEASUREMENTS AND MAIN RESULTS: Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-infinity) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide. CONCLUSION: Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.

A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections.

The objective of this article is to review and evaluate risks and benefits associated with the use of acyclovir in the treatment and prophylaxis of common manifestations of herpes simplex virus (HSV) infections in immunocompetent and immunocompromised patients. Information was found through a MEDLINE search using keywords: herpes simplex virus, genital herpes, herpes labialis, acyclovir and acyclovir. Selected articles were randomised, double-blind, placebo-controlled, clinical trials. 30 such trials involving 3364 persons were evaluated. All articles were reviewed by the authors and the data were extracted and summarised. In both immunocompetent and immunocompromised hosts, acyclovir therapy demonstrated a high degree of clinical efficacy. None of the studies reported statistically significant differences between acyclovir and placebo for mild or major adverse events. This evaluation found that acyclovir is both effective and well tolerated for treatment and prophylaxis of genital, oral and mucocutaneous HSV infections in immunocompetent and immunocompromised patients. In most clinical scenarios. the benefit of acyclovir exceeded any risks by a comfortable margin. The availability of acyclovir as a generic preparation further improves the benefit to cost ratio.

Pharmacodynamics of human immunodeficiency virus type 1 protease inhibitors.

Many factors are involved in the success or failure of antiretroviral therapy. Recent data suggest that there are significant differences in drug absorption and disposition for the protease inhibitor class of antiretroviral drugs, and relationships between plasma concentrations and their antiviral effect have been described. Consequently, the issue of whether therapeutic drug monitoring should be employed for patients receiving treatment with these drugs has arisen. Several criteria must be met before a drug is considered a candidate for therapeutic drug monitoring. These criteria include pharmacological, clinical, and analytic components. Although not all the necessary criteria have yet been met, some of these components have been defined, and additional data are being generated. However, prospectively designed clinical trials must be completed to determine if monitoring protease inhibitor plasma concentrations provides additional clinical benefit to the patient.

An experimental method for the application of lateral muscle loading and its effect on femoral strain distributions.

Experimental models that have been used to evaluate hip loading and the effect of hip implants on bone often use only a head load and abductor load. Anatomic considerations and in vivo measurements have lead several investigators to suggest that these models are inaccurate because they do not incorporate the loads imposed by additional muscles. The aim of this study was to evaluate the strains in the proximal and mid diaphysis of the femur for five hip loading models, one with a head load and abductor load only and four which incorporated lateral muscle loads as well. Head load to body weight load ratios were used to evaluate the physiologic accuracy of these models and strains were compared to determine the extent of strain changes as a function of model complexity. All models which incorporated additional lateral muscle loads more accurately simulated head load to body-weight load ratios than the simple abductor-only model. The model which incorporated a coupled vastus lateralis and iliotibial band load in addition to the abductor load provided the simplest configuration with a reasonable body-weight to head-load ratio.

A comparison of in vitro and in vivo degradation of two CPC strain gauge coatings.

Calcium phosphate ceramic (CPC) coated strain gauges have been used to measure bone strain in animal models for up to 16 weeks and are being developed to collect measurements in patients for periods of 1 year or more. A published surface roughening and heat treating procedure produced improved dry strength and in vivo stability of CPC-gauge interfaces after 16 weeks. The long term bond strength of two CPC-gauge interfaces prepared using the roughening and heat treating process were evaluated after up to 1 year in vitro and in vivo using a lap shear test. The feasibility of using an in vitro test to predict long term in vivo interface changes was established. A blended tricalcium phosphate + hydroxyapatite had a CPC-gauge interface strength which decreased from 6.07 +/- 2.64 MPa at 16 weeks to 4.71 +/- 1.840 MPa after 1 year in Hanks Balanced Salts (HBS). The same coating had a strength that decreased from 8.51 +/- 2.63 MPa at 16 weeks to 5.35 +/- 1 MPa after 1 year in vivo. A soluble calcium enhanced hydroxyapatite had an interface strength of 4.83 +/- 1.106 MPa after 16 weeks and 4.51+/- 1.100 MPa after 1 year in HBS. The same coating had an interface strength of 8.34 +/- 2.40 MPa after 16 weeks and 5.20 +/- 2.00 MPa after 1 year in vivo. Although interface strengths decreased slightly with time in vivo, after 1 year they were in the same strength range as published CPC-bone interface strengths of 4.8 +/- 2.4 MPa. Comparison of in vitro with in vivo results indicated that in vitro results were a good predictor of strength change in the blended CPC coating, but a poorer predictor of strength changes in the soluble calcium-enhanced coating.

Polyethylene particle morphology in synovial fluid of failed knee arthroplasty.

Synovial fluid from the knees of 16 patients undergoing revision knee arthroplasty for aseptic failure was subjected to base digestion and ultrafiltration. Filtered particles were scanned using scanning electron microscopy and analyzed with an image program. Polyethylene particles were identified visually and confirmed with the use of electron diffraction spectroscopy. Averaging more than 1500 particles per patient sample, 25,148 particles were analyzed. This corresponded to a concentration of 3000 polyethylene particles per milliliter of synovial fluid. Three populations of wear debris were identified in the fluid. Small globular particles with a mean area of 75 mu 2 represented 94% of all particles observed. The particles averaged 10 mu in diameter and often were seen in clumps. Long fibrous particles with a mean area of 1164 mu 2 made up 4% of the particle population. Large rhomboidal particles with an area of 557 mu 2 were observed least commonly and comprised the remainder of the particles visualized. All three particle types were observed in each fluid sample regardless of the wear pattern of the retrieved polyethylene liner. There were no differences in absolute particle counts, particle morphologic characteristics, or particle size between patients with and without gross polyethylene wear.

Bone bonding strength of calcium phosphate ceramic coated strain gauges.

Although strain transfer from bone to gauge has been used as an indication of the extent of bone bonding to calcium phosphate ceramic (CPC) coated strain gauges, interface strength measurements have not been reported. In order to develop bone-bonded gauges that remain attached to bone surfaces for long periods, the strength of the CPC-bone interface must be optimized. A shear test to assess the interface strength of the CPC-bone interface was developed using the femora of 120-day-old male rats. The mean interface strength of a blended CPC coating bonded to the femora of the rats for 6 weeks in vivo was 4.8+/-2.4 MPa, and one specimen achieved a strength of nearly 10 MPa. This mean strength value is higher then the CPC-gauge interface strength reported in early studies, but it is lower than recently developed heat treated CPC-gauge interfaces that have average strengths of approximately 7.0+/-2.0 MPa.

Interface strength studies of calcium phosphate ceramic coated strain gauges.

In vivo strain gauging has been used to understand physiological loading and bone remodeling. In early studies, a cyanoacrylate adhesive was used to bond gauges to bone, even though this adhesive is susceptible to biodegradation that results in rapid debonding. Calcium phosphate ceramic (CPC) coated gauges have been successfully bonded to bone for long periods. However, earlier studies noted occasional debonding of coatings from gauges. The goals of this project were to develop a technique to securely bond particles to gauge backings and develop an in vitro test and assess its accuracy in simulating in vivo degradation of this interface. Gauges were heated for different time intervals, roughened with carbide papers, and prepared using layered coatings of polysulfone and CPC particles that varied in size, shape, and crystallinity. They were soaked in solution or placed in muscle pouches of rats for up to 16 weeks. They were then epoxied to fixtures, mounted on an MTS machine, and loaded to failure. Heating and roughening gauge surfaces increased the interface strengths by up to 2000%. In vivo and in vitro testing showed an initial drop in the interface strength, which leveled off to approximately 7.0+/-2.0 MPa.

A mechanical and histomorphometric analysis of bone bonding by hydroxyapatite-coated strain gages.

Identification of the strains controlling bone remodeling is important for determining ways to prevent bone loss due to load deprivation, or implant placement. Long-term monitoring of strains can potentially provide the best information. Glues are resorbed within 2-3 weeks. Two formulations of microcrystalline hydroxyapatite (HA) were used to attach strain gages to rat femora to assess their long-term in vivo strain measurement capability. Seven male rats received HA-coated gages, and 2 animals underwent a sham procedure. The gages were prepared using a published technique and placed on the antero-lateral aspect of the left femora. After 6-7 weeks, the animals were euthanized and both femora explanted. Gages were attached to the right femora with cyanoacrylate. All femora were tested in cantilever bending, then embedded, sectioned, and stained with mineralized bone stain. The undecalcified sections were examined using transmitted and ultraviolet light microscopy. Mechanical testing showed one HA formulation provided 70-100% bonding. Histology showed intimate contact between the gage and bone surface. Histomorphometry indicated increased bone activity under the gage compared to the remaining bone, the controls, and the shams. The results indicate that microcrystalline HAs bond to bone quickly and can allow long term in vivo measurements.

Mucoid impaction following nasal intubation in a child with an upper respiratory infection.

We describe a case of mucoid impaction following nasotracheal intubation in a child with an upper respiratory infection that was successfully treated with a fiberoptic bronchoscope too large to pass through the endotracheal tube lumen. To the best of our knowledge, it is the first report in the anesthesia literature in which the placement of a nasal tracheal tube is implicated as the cause of the mucous obstruction. The physiologic changes that occur with anesthesia and that place patients at increased risk for this phenomenon, as well as the differential diagnosis, treatment, and prevention of this entity, are discussed.