The Contributions of Clinical Pharmacology to HIV Cure Research

Fletcher, Courtney V.; Dyavar, Shetty Ravi; Acharya, Arpan; Byrareddy, Siddappa N.

doi:10.1002/cpt.2237

Cited by 7 publications

(3 citation statements)

References 101 publications

(146 reference statements)

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“…In people with chronic HIV, ART intensification with addition of a single agent, frequently raltegravir, has largely, but not uniformly, been shown to not reduce residual viremia or reservoir size [7,8]. Importantly, tissue reservoirs for HIV may also be pharmacologic sanctuaries for antiretroviral drugs [9]. Therefore, intensification strategies must actually enhance anti-HIV activity at the tissue source of residual viremia, which was not demonstrated.…”

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confidence: 99%

Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression

Fletcher

Kroon

Schacker

et al. 2022

Aids

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Objective:The ability of antiretroviral drugs to penetrate and suppress viral replication in tissue reservoir sites is critical for HIV remission. We evaluated antiretroviral concentrations in lymph nodes and their impact on HIV transcription.Methods:Participants of the RV254/SEARCH010 Acute HIV Infection Cohort in Thailand were enrolled. Group 1 (n = 6) initiated and continued antiretrovirals with two nucleoside reverse transcriptase inhibitors (NRTIs), dolutegravir (DTG) and mar- aviroc (MVC). Group 2 (n = 12) initiated antiretrovirals with two NRTIs as well as efavirenz and were switched to two NRTIs as well as DTG. Antiretroviral concentrations were measured by mass spectroscopy. HIV RNA+ and DNA+ cells were measured by in-situ hybridization.Results:All participants were MSM. At lymph node biopsy, all had plasma HIV RNA less than 20 copies/ml. Group 2 had longer durations of antiretroviral and DTG use (medians of 135 and 63 weeks, respectively) compared with Group 1 (median 44 weeks for both). TFV-DP, 3TC-TP, DTG and MVC were quantifiable in all lymph node samples from participants receiving those drugs versus carbovir-triphosphate (CBV-TP) in four out of 14. Median ratios of lymph node to peripheral blood concentrations were DTG, 0.014; MVC, 6.9; CBV-TP, 0.38; 3TC-TP, 0.32; and TFV-DP, 3.78. Median inhibitory quotients [ratios of lymph node concentrations to in-vitro inhibitory levels (IC50-or-90)] were DTG, 0.8; MVC, 38.8; CBV-TP, 0.5; 3TC- TP, 4.1; and TFV-DP, 1.8. Ongoing viral transcription was detected in lymph node of all participants. Median lymph node RNA+ cells were 71 350 versus 99 750 cells/g for Groups 1 and 2, respectively (P = 0.111).Conclusion:MVC has enhanced lymph node penetration and thereby may contribute to more complete viral suppression in the lymph node.

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confidence: 99%

Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression

Fletcher

Kroon

Schacker

et al. 2022

Aids

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“…Finally, our group has provided a proof-of-concept that Vδ2 T cells may be incorporated into current strategies for HIV cure within virally suppressed people living with HIV [ 71 , 72 ]. One approach utilized in HIV cure strategies encompasses reactivation of latent virus using small compounds generally called latency reversing agents and boosting immune responses [ 73 , 74 , 75 , 76 , 77 , 78 ]. We demonstrated that autologous expanded Vδ2 T cells mediated killing of latently HIV-infected CD4+ T cell reservoirs upon reactivation.…”

Section: Clinical Applications Of Vδ2 T Cell Immunotherapymentioning

confidence: 99%

Human Vδ2 T Cells and Their Versatility for Immunotherapeutic Approaches

Sanz

Mann

Chitrakar

et al. 2022

Cells

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Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential

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“…3233 Additionally, strategies to cure HIV are complicated in part by pharmacological challenges (eg, limited drug distribution at effector sites such as in tissues, inadequate therapeutic efficacy, and unfavorable drug toxicity). 3435…”

Section: Introductionmentioning

confidence: 99%

HIV Pharmacology Data Repository (PDR): Setting the New Information Sharing Standard for Pharmacokinetic Studies

Tompkins

Kapeljushnik

Hubal

et al. 2023

Preprint

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Clinical therapeutics are becoming increasingly reliant on data science and computational data analytical tools to predict drug behavior in unobserved conditions or populations. These in silico approaches, collectively termed 'pharmacometrics', derive biological meaning from the analysis of pooled drug concentration vs. time (CvT) datasets. However, the field lacks standardization for pharmacokinetic (PK) data description and sharing, instead requiring deep dives into the literature and expert data annotation for aggregate data mining. Here we introduce a minimum information sharing standard for PK studies composed of three categories (Intervention, System, and Effects) and implement this standard in the development of a web-based PK database: the HIV Pharmacology Data Repository (PDR). We demonstrate the utility of the HIV PDR by computational modeling of aggregated and curated CvT data extracted from the HIV PDR.

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The Contributions of Clinical Pharmacology to HIV Cure Research

Abstract: AdherenceLow drug concentrations and low ART adherence, predicted future viremia in PLWH, as measured by quantitation of tenofovir-diphosphate in dried blood spots. Viral blips and low-level viremia are associated with a larger reservoir size.

Cited by 7 publications

References 101 publications

Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression

Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression

Human Vδ2 T Cells and Their Versatility for Immunotherapeutic Approaches

HIV Pharmacology Data Repository (PDR): Setting the New Information Sharing Standard for Pharmacokinetic Studies

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