Imaging and biopsy of HIV-infected individuals undergoing analytic treatment interruption

Background HIV persistence during antiretroviral therapy (ART) is the principal obstacle to cure. Lymphoid tissue is a compartment for HIV, but mechanisms of persistence during ART and viral rebound when ART is interrupted are inadequately understood. Metabolic activity in lymphoid tissue of patients on long-term ART is relatively low, and increases when ART is stopped. Increases in metabolic activity can be detected by 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and may represent sites of HIV replication or immune activation in response to HIV replication. Methods FDG-PET imaging will be used to identify areas of high and low metabolic uptake in lymphoid tissue of individuals undergoing long-term ART. Baseline tissue samples will be collected. Participants will then be randomized 1:1 to continue or interrupt ART via analytic treatment interruption (ATI). Image-guided biopsy will be repeated 10 days after ATI initiation. After ART restart criteria are met, image-guided biopsy will be repeated once viral suppression is re-achieved. Participants who continued ART will have a second FDG-PET and biopsies 12–16 weeks after the first. Genetic characteristics of HIV populations in areas of high and low FDG uptake will be assesed. Optional assessments of non-lymphoid anatomic compartments may be performed to evaluate HIV populations in distinct anatomic compartments. Anticipated results We anticipate that PET standardized uptake values (SUV) will correlate with HIV viral RNA in biopsies of those regions and that lymph nodes with high SUV will have more viral RNA than those with low SUV within a patient. Individuals who undergo ATI are expected to have diverse viral populations upon viral rebound in lymphoid tissue. HIV populations in tissues may initially be phylogenetically diverse after ATI, with emergence of dominant viral species (clone) over time in plasma. Dominant viral species may represent the same HIV population seen before ATI. Discussion This study will allow us to explore utility of PET for identification of HIV infected cells and determine whether high FDG uptake respresents areas of HIV replication, immune activation or both. We will also characterize HIV infected cell populations in different anatomic locations. The protocol will represent a platform to investigate persistence and agents that may target HIV populations. Study protocol registration Identifier: NCT05419024.

[1]  J. Mascola,et al.  First-in-human immunoPET imaging of HIV-1 infection using 89Zr-labeled VRC01 broadly neutralizing antibody , 2022, Nature Communications.

[2]  R. Boellaard,et al.  18F-FDG PET baseline radiomics features improve the prediction of treatment outcome in diffuse large B-cell lymphoma , 2021, European Journal of Nuclear Medicine and Molecular Imaging.

[3]  R. Slart,et al.  Comparison and validation of FDG-PET/CT scores for polymyalgia rheumatica , 2021, Rheumatology.

[4]  Y. Yeh,et al.  Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expression , 2021, Proceedings of the National Academy of Sciences.

[5]  D. Lauffenburger,et al.  Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features , 2021, mBio.

[6]  P. Price,et al.  Total-Body PET Imaging in Infectious Diseases. , 2020, PET clinics.

[7]  J. Dorfman,et al.  author-version of: Compartmentalization and clonal amplification of HIV-1 in the male genital tract characterized using next-generation sequencing , 2022 .

[8]  S. Hughes,et al.  HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus , 2020, bioRxiv.

[9]  Z. Debyser,et al.  Block-And-Lock Strategies to Cure HIV Infection , 2020, Viruses.

[10]  R. Bosch,et al.  Time to viral rebound and safety after antiretroviral treatment interruption in postpartum women compared to men. , 2019, AIDS.

[11]  S. Q. Brunetto,et al.  Proposal for a Quantitative 18F-FDG PET/CT Metabolic Parameter to Assess the Intensity of Bone Involvement in Multiple Myeloma , 2019, Scientific Reports.

[12]  S. Hughes,et al.  HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy. , 2019, The Journal of clinical investigation.

[13]  M. Beg,et al.  Quantifying brain metabolism from FDG‐PET images into a probability of Alzheimer's dementia score , 2019, Human brain mapping.

[14]  A. Lazzarin,et al.  Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study). , 2019, The Journal of antimicrobial chemotherapy.

[15]  J. Mullins,et al.  Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression. , 2019, AIDS research and human retroviruses.

[16]  T. Chun,et al.  Effect of Anti‐CD4 Antibody UB‐421 on HIV‐1 Rebound after Treatment Interruption , 2019, The New England journal of medicine.

[17]  B. Walker,et al.  Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting. , 2019, The lancet. HIV.

[18]  L. Trautmann,et al.  Modeling HIV-1 Latency Using Primary CD4+ T Cells from Virally Suppressed HIV-1-Infected Individuals on Antiretroviral Therapy , 2019, Journal of Virology.

[19]  L. Morris,et al.  Evidence for both Intermittent and Persistent Compartmentalization of HIV-1 in the Female Genital Tract , 2019, Journal of Virology.

[20]  D. Hammoud,et al.  Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND) , 2019, Current HIV/AIDS Reports.

[21]  R. Siliciano,et al.  A novel quantitative approach for measuring the reservoir of latent HIV-1 proviruses , 2019, Nature.

[22]  Cornelis H. Slump,et al.  Repeatability of 18F‐FDG PET radiomic features: A phantom study to explore sensitivity to image reconstruction settings, noise, and delineation method , 2018, Medical physics.

[23]  F. Maldarelli,et al.  The role of integration and clonal expansion in HIV infection: live long and prosper , 2018, Retrovirology.

[24]  Bryan R. Smith,et al.  Global and regional brain hypometabolism on FDG-PET in treated HIV-infected individuals , 2018, Neurology.

[25]  L. Dodd,et al.  Increased Metabolic Activity on 18F-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography in Human Immunodeficiency Virus–Associated Immune Reconstitution Inflammatory Syndrome , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  L. Dodd,et al.  Brain 18F-FDG PET of SIV-infected macaques after treatment interruption or initiation , 2018, Journal of Neuroinflammation.

[27]  M. St. Claire,et al.  Total body CD4+ T cell dynamics in treated and untreated SIV infection revealed by in vivo imaging. , 2018, JCI insight.

[28]  E. Connick,et al.  The B-Cell Follicle in HIV Infection: Barrier to a Cure , 2018, Front. Immunol..

[29]  K. Busman-Sahay,et al.  Next-generation in situ hybridization approaches to define and quantify HIV and SIV reservoirs in tissue microenvironments , 2018, Retrovirology.

[30]  R. Dierckx,et al.  The Role of Nuclear Medicine in the Staging and Management of Human Immune Deficiency Virus Infection and Associated Diseases , 2017, Nuclear Medicine and Molecular Imaging.

[31]  A. Kjaer,et al.  Whole-Body 18F-FDG PET/CT Is Superior to CT as First-Line Diagnostic Imaging in Patients Referred with Serious Nonspecific Symptoms or Signs of Cancer: A Randomized Prospective Study of 200 Patients , 2017, The Journal of Nuclear Medicine.

[32]  G. Learn,et al.  Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. , 2016, The New England journal of medicine.

[33]  B. Barlogie,et al.  Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma , 2016, Clinical Cancer Research.

[34]  Michael T. Lu,et al.  Effects of Antiretroviral Therapy on Immune Function and Arterial Inflammation in Treatment-Naive Patients With Human Immunodeficiency Virus Infection. , 2016, JAMA cardiology.

[35]  Nico Pfeifer,et al.  HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption , 2016, Nature.

[36]  A. Blaxhult,et al.  Viral blips during suppressive antiretroviral treatment are associated with high baseline HIV-1 RNA levels , 2016, BMC Infectious Diseases.

[37]  F. Vaida,et al.  Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1-Infected Adults Receiving Long-term Antiretroviral Therapy. , 2016, The Journal of infectious diseases.

[38]  M. Lederman,et al.  The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption , 2015, AIDS.

[39]  R. Slart,et al.  Different Scoring Methods of FDG PET/CT in Giant Cell Arteritis , 2015, Medicine.

[40]  A. Scarsbrook,et al.  FDG PET/CT in infection and inflammation--current and emerging clinical applications. , 2015, Clinical radiology.

[41]  Y. Sakamoto,et al.  Advantages of FDG-PET/CT over CT alone in the preoperative assessment of lymph node metastasis in patients with esophageal cancer , 2015, Surgery Today.

[42]  A. Haase,et al.  Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption , 2015, Proceedings of the National Academy of Sciences.

[43]  Eric J. W. Visser,et al.  FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0 , 2014, European Journal of Nuclear Medicine and Molecular Imaging.

[44]  D. Podzamczer,et al.  Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. , 2014, The Lancet. Infectious diseases.

[45]  J. Mellors,et al.  Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy , 2014, PLoS pathogens.

[46]  Steve Kaye,et al.  Short-course antiretroviral therapy in primary HIV infection. , 2013, The New England journal of medicine.

[47]  Bradford J. Wood,et al.  Multimodality Image Fusion–Guided Procedures: Technique, Accuracy, and Applications , 2012, CardioVascular and Interventional Radiology.

[48]  M. Merino,et al.  Magnetic resonance imaging-guided volumetric ablation of symptomatic leiomyomata: correlation of imaging with histology. , 2012, Journal of vascular and interventional radiology : JVIR.

[49]  S Spudich,et al.  HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. , 2012, Cold Spring Harbor perspectives in medicine.

[50]  A. Haase,et al.  Lymphoid Tissue Damage in HIV-1 Infection Depletes Naïve T Cells and Limits T Cell Reconstitution after Antiretroviral Therapy , 2012, PLoS pathogens.

[51]  R. Lhommel,et al.  HIGH FDG UPTAKE ON FDG-PET SCAN IN HIV-1 INFECTED PATIENT WITH ADVANCED DISEASE , 2011, Acta clinica Belgica.

[52]  Samuel Kadoury,et al.  Real-time FDG PET guidance during biopsies and radiofrequency ablation using multimodality fusion with electromagnetic navigation. , 2011, Radiology.

[53]  T Reunala,et al.  Patient‐Oriented SCORAD (PO‐SCORAD): a new self‐assessment scale in atopic dermatitis validated in Europe , 2011, Allergy.

[54]  Sheng Xu,et al.  Clinical utility of real-time fusion guidance for biopsy and ablation. , 2011, Journal of vascular and interventional radiology : JVIR.

[55]  C. Rouzioux,et al.  A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption, independently of the CD4 nadir , 2010, Journal of medical virology.

[56]  R. Schooley,et al.  AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein. , 2010, The Journal of infectious diseases.

[57]  Ankur Kapoor,et al.  Navigation systems for ablation. , 2010, Journal of vascular and interventional radiology : JVIR.

[58]  T. Murakami,et al.  FDG PET/CT versus CT, MR imaging, and 67Ga scintigraphy in the posttherapy evaluation of malignant lymphoma. , 2010, Radiographics : a review publication of the Radiological Society of North America, Inc.

[59]  Bradford J Wood,et al.  Image-guided adrenal and renal biopsy. , 2010, Techniques in vascular and interventional radiology.

[60]  M. Hirsch,et al.  Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment , 2009, AIDS.

[61]  G. Lucignani,et al.  FDG-PET imaging in HIV-infected subjects: relation with therapy and immunovirological variables , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[62]  J. Estes.  Role of collagen deposition in lymphatic tissues and immune reconstruction during HIV-1 and SIV infections , 2009, Current HIV/AIDS reports.

[63]  M. McKenna,et al.  Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years--United States, 2008. , 2008, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[64]  B. Wigdahl,et al.  HIV-1 Infection of Bone Marrow Hematopoietic Progenitor Cells and Their Role in Trafficking and Viral Dissemination , 2008, PLoS pathogens.

[65]  A. Haase,et al.  The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche. , 2008, Seminars in immunology.

[66]  B. Reider.  Live Long and Prosper , 2008, The American journal of sports medicine.

[67]  Joseph A Kovacs,et al.  ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia , 2007, PLoS pathogens.

[68]  J Darbyshire,et al.  CD4+ count-guided interruption of antiretroviral treatment. , 2006, The New England journal of medicine.

[69]  Richard Davey,et al.  Fluorodeoxyglucose imaging in healthy subjects with HIV infection: impact of disease stage and therapy on pattern of nodal activation , 2006, AIDS.

[70]  C. Rouzioux,et al.  Structured Treatment Interruptions in Primary HIV-1 Infection: The ANRS 100 PRIMSTOP Trial , 2005, Journal of acquired immune deficiency syndromes.

[71]  R. Hawkins,et al.  Advances in positron emission tomography imaging for the GI tract. , 2002, Gastrointestinal endoscopy.

[72]  D Delbeke,et al.  Positron emission tomography imaging in oncology. , 2001, Radiologic clinics of North America.

[73]  R. Siliciano,et al.  Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. , 2000, The Journal of infectious diseases.

[74]  M Schwaiger,et al.  Quantitative assessment of tumor metabolism using FDG-PET imaging. , 2000, Nuclear medicine and biology.

[75]  M. Saag,et al.  Recurrence of the Acute HIV Syndrome after Interruption of Antiretroviral Therapy in a Patient with Chronic HIV Infection: A Case Report , 2000, Annals of Internal Medicine.

[76]  R. Pyzalski,et al.  Whole body positron emission tomography imaging of activated lymphoid tissues during acute simian-human immunodeficiency virus 89.6PD infection in rhesus macaques. , 2000, Virology.

[77]  R. Siliciano,et al.  Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection , 1997, Nature.

[78]  L. Staudt,et al.  Human immunodeficiency virus type 1 infection of H9 cells induces increased glucose transporter expression , 1996, Journal of virology.

[79]  Robert F. Siliciano,et al.  In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency , 1995, Nature Medicine.

[80]  K. Maull,et al.  Cholecystectomy: to drain or not to drain. A randomized prospective study of 200 patients. , 1978, The Journal of surgical research.

[81]  The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption: Erratum. , 2016, AIDS.

[82]  C. B. Hare,et al.  The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals. , 2012, The Journal of infectious diseases.

[83]  Baris Turkbey,et al.  Use of patient-specific MRI-based prostate mold for validation of multiparametric MRI in localization of prostate cancer. , 2012, Urology.

[84]  G. Shaw,et al.  HIV transmission. , 2012, Cold Spring Harbor perspectives in medicine.

[85]  B. Thiers,et al.  CD4+ Count–Guided Interruption of Antiretroviral Treatment , 2007 .

[86]  Henry J. Kaiser,et al.  Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and Henry J. Kaiser Family Foundation. , 1998, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[87]  D. C. Henckel,et al.  Case report. , 1995, Journal.

[88]  L Wallden,et al.  Need for standardization , 1970 .