Suboptimal immune reconstitution despite HIV suppression on ART - - PowerPoint PPT Presentation

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Suboptimal immune reconstitution despite HIV suppression on ART - - PowerPoint PPT Presentation

Apr 10, 2024 148 likes •397 views

Suboptimal immune reconstitution despite HIV suppression on ART Connie J. Kim, MSc, PhD Scientific Associate I Toronto General Hospital Supervisors: Drs. Sharon Walmsley and Rupert Kaul Disclosure Employee of Theratechnologies Medical

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Suboptimal immune reconstitution despite HIV suppression on ART

Connie J. Kim, MSc, PhD Scientific Associate I Toronto General Hospital

Supervisors: Drs. Sharon Walmsley and Rupert Kaul

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Disclosure

  • Employee of Theratechnologies
  • Medical Science Liaison in the division of Medical Affairs
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Outline

  • Background: Definition and prevalence
  • Clinical consequences
  • Mechanism of poor CD4 recovery
  • Treatment options
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Terminology: there are many…

  • Immune non‐responder (INR)
  • Compared to immune responders
  • Discordant immune response
  • Suboptimal/poor immune reconstitution
  • Incomplete immune recovery
  • Etc…
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Immune non‐responder definition

  • 2. HIV suppression
  • 1. HIV medication

Norris, CID 2016 Kelly, PloS One 2016

Immune responder Immune non‐responder Viral load (c/ml)

  • 3. CD4 count
  • 4. Time

CD4 count (/mm3)

There were at least 14 different definitions for INR and currently there is no consensus to their definition1

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Time course of INR compared to immune responder after starting ART

Time CD4 count (cell/ml)

200 500 0 month ART Immune Responder (IR) Immune Non‐Responder (INR) 350 20‐30 cells per month 6 month 5‐10 cells per month 12‐24 months

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Predictors of INR

  • CD4 count when starting ART
  • Older age
  • >50, 4x more likely than <30 years of age
  • Duration of ART
  • Being on ART longer may increase CD4 count above threshold
  • Viral load before starting ART does not predict INR

Engsig, CID 2014

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Starting ART early is important

CD4 count when starting ART (cells/mm3) % of INR (<500 cells/mm3) >300 Less than 5% 100‐200 25% <100 44%

Follow‐up after ART for approximately 7.5 years

1Kelley et al. CID 2009

Prevalence of INR varies depending on the criteria used in the study 15‐30%

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An update on CD4 count threshold

  • Using a CD4 threshold of 400 cells/mm3 best selected for HIV+

individuals with poorer immune variables

  • Immune activation and CD4 T cell death
  • Better predictor of INR than change of CD4 count over time
  • They are a heterogeneous group
  • 22% of INRs had a similar immune profile to responders

Perez‐Santiago et al. AIDS 2016

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Outline

  • Background: Definition and prevalence
  • Clinical consequences
  • Mechanism of poor CD4 recovery
  • Treatment options
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INR and mortality

  • INR status is associated with

increased mortality1

  • Non‐AIDS defining causes
  • Hepatitis
  • Non‐AIDS cancer
  • Six of 10 studies reported higher

risk of mortality compared to responders2

  • Range of risk ratio 1.0‐4.29

1Engsig, CID 2014 2Kelly, PloS One 2016

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Risk of AIDS and serious non‐AIDS events in INRs

  • Mixed results from a systematic

review

  • This likely depends on the criteria
  • f INR
  • Non‐AIDS events were assessed

in 1 study (Baker)

  • Similar between INR and IRs
  • Small study with only few events

Kelly, PloS One 2016

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Outline

  • Background: Definition and prevalence
  • Clinical consequences
  • Mechanism of poor CD4 recovery
  • Treatment options
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Immune factors that contribute to INR

Low number of progenitor cells

Low input

Thymus & Lymph tissue

Poor T cell output ‐ Architecture (fibrosis) ‐ Poor T cell migration/maturation ‐ Quantity and quality of cells

Low production

Poor CD4 T cell survival ‐ Persistent T cell activation ‐ Inflammation (microbial translocation, low level viremia, etc) ‐ Cell exhaustion and rapid cell death

x x x

Poor maintenance

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INR vs IR: immunology

  • INR have higher CD8 T cell activation1
  • Nadir CD4 count <350
  • IRs >350 while INRs were <350 after 2

years of suppressive ART

  • INR characterized by2
  • Increased CD4 T cell activation

(HLADR+CD38+)

  • Pro‐inflammatory CD4 T cells (TNF and

IFNg+)

  • Exhausted phenotype T cells (PD‐1+)

1Rousseau, unpublished; 2Ramirez, AIDS 2016

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Outline

  • Background: Definition and prevalence
  • Clinical consequences
  • Mechanism of poor CD4 recovery
  • Treatment & management strategies
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Changing HIV medications

  • Being on various HIV drug classes do not improve CD4 count
  • n=3293, Swiss cohort from 1996 to 2007 and followed up for >2 years
  • PI boosted, PI unboosted, NNRTI
  • Being on different drug classes did not impact CD4 recovery
  • Newer drugs: Integrase inhibitors? Entry inhibitors? Maturation

inhibitors?

Khanna et al. CID 2008

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No pharmacological treatment for INR

  • Anti‐inflammatory agents
  • Treating co‐infections
  • Reducing microbial translocation
  • Reduce viral replication
  • Thymic stimulant

Low number of progenitor cells

Low input

Thymus & Lymph tissue

Low production

 x x x

Poor maintenance

  • Stimulate naïve

T cell production

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Treatment options to increase CD4 count

  • IL‐7 to regulate T cell homeostasis (INSPIRE studies)
  • Low dose: Increased CD4 count by 28% by week 48 (216  282 cells/mm3)
  • High dose: increased CD4 count by 75% by week 48 (239  403 cells/mm3)
  • Increased cells trafficking to the gut
  • Safety studies conducted; no clinical outcome data
  • IL‐2 to regulate T cell homeostasis (SILCAAT and ESPRIT studies)
  • Increased CD4 count but no clinical benefit (death or AIDS diagnoses)
  • Canadian studies:
  • Probiotics to improve gut health and reduce inflammation (Rupert Kaul)
  • Ongoing study
  • Chloroquine (anti‐inflammatory agent)
  • No improvement in CD4 recovery after 24 weeks
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Acknowledgements

  • Drs. Rupert Kaul and Sharon Walmsley
  • Rodney Rousseau (Probiotic study graduate student)
  • Robert Reinhard
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Clinical recommendations

  • Start ART early with emphasis on adherence
  • Monitor subclinical opportunistic infections (CMV, TB)
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Treatment options aimed to reduce immune activation and inflammation

  • Reduce viral set point
  • Addition of raltegravir to standard ART
  • Treat underlying co‐infection
  • CMV treatment with valganciclovir did NOT improve CD4 count
  • Reduce microbial translocation
  • Probiotics to improve gut immune health
  • One study showed no benefit to CD4 recovery
  • Our study
  • Anti‐inflammatory agents
  • Statins reduced inflammation but no evidence of CD4 recovery
  • Quinolones marginally reduced inflammation
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The PROOV IT study: probiotic study

  • Overarching question: can probiotics enhance gut immune

restoration and reduce inflammation?

  • PROOV IT II study: can probiotics increase CD4 count in INRs?
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Probiotic: Visbiome (formerly VSL#3)

  • Highest concentration probiotic product
  • Previously studied in human and animal models of HIV/SIV
  • Health Canada approved for pouchitis and Ulcerative colitis
  • Not indicated for HIV