Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults

Baheti, Gautam; King, Jennifer R.; Acosta, Edward P.; Fletcher, Courtney V.

doi:10.1097/qad.0b013e32835a9a2d

Cited by 12 publications

(12 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FTCtp levels were similar to or lower than those found in healthy adults (30,31), but reference data for children are not available. The observed levels of PMPAdp in three animals were much higher than has been reported for HIV-infected children (28), possibly reflecting a higher dose used in the macaques than is recommended for pediatric clinical practice. We then assessed drug penetration in lymph nodes (LN), spleen, colon, and brain using LS-MS/MS and IR-MALDESI, a technique that allows the spatial visualization of the anatomic distribution of the drugs within the tissue (26).…”

Section: Drug Concentrations In Blood and Tissues Of Art-treated Siv-mentioning

confidence: 54%

“…3A. These measured values are below published ranges for the same drugs dosed orally in children (27)(28)(29); however, it is important to recall that plasma viral loads were below the limit of detection at the time of this analysis, meaning that the combination ART regimen was effective in suppressing viremia in infant RMs. In the cerebrospinal fluid (CSF), trough levels of PMPA and DTG were lower than in plasma, with levels of DTG near or below the limit of quantification of the LS-MS/MS method in three of four animals (Fig.…”

Section: Drug Concentrations In Blood and Tissues Of Art-treated Siv-mentioning

confidence: 62%

See 1 more Smart Citation

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

Mavigner

Habib

Deléage

et al. 2018

J Virol

View full text Add to dashboard Cite

Worldwide, nearly two million children are infected with human immunodeficiency virus (HIV), with breastfeeding accounting for the majority of contemporary HIV transmissions. Antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality but is not curative. The main barrier to a cure is persistence of latent HIV in long-lived reservoirs. However, our understanding of the cellular and anatomic sources of the HIV reservoir during infancy and childhood is limited. Here, we developed a pediatric model of ART suppression in orally simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) infants, with measurement of virus persistence in blood and tissues after 6 to 9 months of ART. Cross-sectional analyses were conducted to compare SIV RNA and DNA levels in adult and infant RMs naive to treatment and on ART. We demonstrate efficient viral suppression following ART initiation in SIV-infected RM infants with sustained undetectable plasma viral loads in the setting of heterogeneous penetration of ART into lymphoid and gastrointestinal tissues and low drug levels in the brain. We further show reduction in SIV RNA and DNA on ART in lymphoid tissues of both infant and adult RMs but stable (albeit low) levels of SIV RNA and DNA in the brains of viremic and ART-suppressed infants. Finally, we report a large contribution of naive CD4 T cells to the total CD4 reservoir of SIV in blood and lymph nodes of ART-suppressed RM infants that differs from what we show in adults. These results reveal important aspects of HIV/SIV persistence in infants and provide insight into strategic targets for cure interventions in a pediatric population. While antiretroviral therapy (ART) can reduce HIV replication, the virus cannot be eradicated from an infected individual, and our incomplete understanding of HIV persistence in reservoirs greatly complicates the generation of a cure for HIV infection. Given the immaturity of the infant immune system, it is critically important to study HIV reservoirs specifically in this population. Here, we established a pediatric animal model to simulate breastfeeding transmission and study SIV reservoirs in rhesus macaque (RM) infants. Our study demonstrates that ART can be safely administered to infant RMs for prolonged periods and that it efficiently controls viral replication in this model. SIV persistence was shown in blood and tissues, with similar anatomic distributions of SIV reservoirs in infant and adult RMs. However, in the peripheral blood and lymph nodes, a greater contribution of the naive CD4 T cells to the SIV reservoir was observed in infants than in adults.

show abstract

Section: Drug Concentrations In Blood and Tissues Of Art-treated Siv-mentioning

confidence: 54%

Section: Drug Concentrations In Blood and Tissues Of Art-treated Siv-mentioning

confidence: 62%

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

Mavigner

Habib

Deléage

et al. 2018

J Virol

View full text Add to dashboard Cite

show abstract

“…Notwithstanding, it should be noted that ultimate performance of antiretroviral therapies are thought to be highly dependent on intracellular drug concentrations in HIV target cells [30, 31], and the active metabolites of some NRTIs are known to have long intracellular half-lives [32, 33]. However, given the enthusiasm for the LA approach in adolescence, it is worthy of consideration that at least some of the NRTI metabolites have been reported to be almost 2-fold lower in patients under the age of 25 [34]. …”

Section: The Conceptual Basis For Long-acting Drug Delivery Of Antmentioning

confidence: 99%

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

120

102

View full text Add to dashboard Cite

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

show abstract

“…These complexities contribute to nonlinearities in the pharmacokinetics (PK) relationship between plasma and intracellular TFV-DP [5–7]. Currently, many studies have characterized the PK of plasma TFV/FTC [8–15] and intracellular TFV-DP/FTC-TP [16–22], individually. However, only a few PK link models have investigated the relationship between the plasma TFV and the intracellular TFV-DP, all of which used steady-state observations only.…”

Section: Introductionmentioning

confidence: 99%

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

et al. 2016

View full text Add to dashboard Cite

The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

show abstract

Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults

Cited by 12 publications

References 20 publications

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

Contact Info

Product

Resources

About