Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

The incidence of HIV remains alarmingly high in many parts of the world. Prophylactic use of antiretrovirals, capable of concentrating in the anatomical sites of transmission, may reduce the risk of infection after an unprotected sexual exposure. To date, orally and topically administered antiretrovirals have exhibited variable success in preventing HIV transmission in large-scale clinical trials. Antiretroviral mucosal pharmacokinetics may help explain the outcomes of these investigations. Penetration and accumulation of antiretrovirals into sites of transmission can influence dosing strategies and pre-exposure prophylaxis clinical trial design. Antiretroviral tissue distribution varies widely within and between drug classes, attributed in part to their physicochemical properties and tissue-specific drug transporter expression. Nucleoside (-tide) reverse transcriptase inhibitors, the CCR5 antagonist maraviroc, and the integrase inhibitor raltegravir demonstrate the highest penetration into the male and female reproductive tracts and colorectal tissue relative to blood. This review will describe antiretroviral exposure in anatomic sites of transmission, and place these findings in context with the prevention of HIV and the efficacy of pre-exposure prophylactic strategies

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations

Fluoroquinolones and the Risk of Serious Arrhythmia

In lieu of an abstract, here is the letter\u27s first paragraph: TO THE EDITOR—We read with great interest the recent article by Lapi et al in the 1 December 2012 issue of Clinical Infectious Diseases, which aimed to address the clinical conundrum regarding the risk of serious arrhythmia attributed to fluoroquinolone exposure [1]. In this article the authors concluded that fluoroquinolones, in particular gatifloxacin, moxifloxacin, and ciprofloxacin, are associated with increased rates of serious arrhythmia. We believe readers should interpret these conclusions cautiously as the authors’ conclusions are not supported by the methods employed and the results presented

Tenofovir/emtricitabine metabolites and endogenous nucleotide exposures are associated with p16INK4a expression in subjects on combination therapy

HIV may amplify immunologic, physiologic, and functional changes of aging. We determined associations of frailty phenotype, a T-cell senescence marker (p16INK4a expression), age, and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV), and ritonavir (RTV)

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16^INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

<div><p>Objectives</p><p>As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16^INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16^INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations.</p><p>Methods</p><p>Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16^INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16^INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures.</p><p>Results</p><p>Enrolled participants had a median age of 48 years (range 23–73). There were no significant associations between p16^INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1β, age and TFV-diphosphate exposures.</p><p>Conclusions</p><p>In this clinical evaluation, we found no relationships between p16^INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16^INK4a association with decreased IM/EN exposures in these HIV-infected participants.</p></div

Boxplots of measured cytokine concentrations.

<p>Boxplots of measured cytokine concentrations.</p

Scatterplots of p16^INK4a expression versus cytokine concentrations.

<p>Observations with quantifiable cytokine concentrations are displayed as blue circles; concentrations below the LLQ are displayed as red + symbols. Cytokine concentrations and p16^INK4a expression were natural-log transformed and log₂ transformed, respectively. A descriptive LOESS curve is plotted handling below LLQ values as observed. Correlation estimates were less than or equal to 0.22 for all associations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168709#pone.0168709.t001" target="_blank">Table 1</a>). LLQ, lower limit of quantification.</p

Elastic net results for TFV-dp AUC, FTC-tp AUC, dATP AUC, and dCTP AUC

<p>Elastic net results for TFV-dp AUC, FTC-tp AUC, dATP AUC, and dCTP AUC</p

Correlation between natural-log transformed cytokines and log₂ transformed p16^INK4a expression.

<p>Correlation between natural-log transformed cytokines and log₂ transformed p16^INK4a expression.</p