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 Science Liaison in the division of Medical Affairs
Outline Background: Definition and prevalence Clinical consequences Mechanism of poor CD4 recovery Treatment options
Terminology: there are many… • Immune non‐responder (INR) • Compared to immune responders • Discordant immune response • Suboptimal/poor immune reconstitution • Incomplete immune recovery • Etc…
Immune non‐responder definition Immune non‐responder Immune responder Viral load (c/ml) 1. HIV medication 2. HIV suppression There were at least 14 different definitions for INR and currently there is no consensus to their definition 1 CD4 count (/mm 3 ) 3. CD4 count 4. Time Norris, CID 2016 Kelly, PloS One 2016
Time course of INR compared to immune responder after starting ART 5‐10 cells per month Immune Responder 20‐30 cells CD4 count (cell/ml) (IR) per month 500 350 Immune Non‐Responder (INR) 200 0 month Time 6 month 12‐24 months ART
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
Starting ART early is important CD4 count when starting ART % of INR (cells/mm 3 ) (<500 cells/mm 3 ) >300 Less than 5% 100‐200 25% <100 44% Follow‐up after ART for approximately 7.5 years Prevalence of INR varies depending on the criteria used in the study 15‐30% 1 Kelley et al. CID 2009
An update on CD4 count threshold • Using a CD4 threshold of 400 cells/mm 3 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
Outline Background: Definition and prevalence Clinical consequences Mechanism of poor CD4 recovery Treatment options
INR and mortality • INR status is associated with increased mortality 1 • Non‐AIDS defining causes • Hepatitis • Non‐AIDS cancer • Six of 10 studies reported higher risk of mortality compared to responders 2 • Range of risk ratio 1.0‐4.29 1 Engsig, CID 2014 2 Kelly, PloS One 2016
Risk of AIDS and serious non‐AIDS events in INRs • Mixed results from a systematic review • This likely depends on the criteria of 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
Outline Background: Definition and prevalence Clinical consequences Mechanism of poor CD4 recovery Treatment options
Immune factors that contribute to INR Low input Low production Poor maintenance x x Thymus & x Lymph tissue Poor CD4 T cell survival Poor T cell output Low number of ‐ Persistent T cell activation progenitor cells ‐ Architecture (fibrosis) ‐ Inflammation (microbial ‐ Poor T cell migration/maturation translocation, low level viremia, ‐ Quantity and quality of cells etc) ‐ Cell exhaustion and rapid cell death
INR vs IR: immunology • INR have higher CD8 T cell activation 1 • Nadir CD4 count <350 • IRs >350 while INRs were <350 after 2 years of suppressive ART • INR characterized by 2 • Increased CD4 T cell activation (HLADR+CD38+) • Pro‐inflammatory CD4 T cells (TNF and IFNg+) • Exhausted phenotype T cells (PD‐1+) 1 Rousseau, unpublished; 2 Ramirez, AIDS 2016
Outline Background: Definition and prevalence Clinical consequences Mechanism of poor CD4 recovery Treatment & management strategies
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
No pharmacological treatment for INR Low input Low production Poor maintenance Thymus & x x Lymph x tissue Low number of progenitor cells • Anti‐inflammatory agents • Thymic stimulant • Treating co‐infections • Reducing microbial translocation • Stimulate naïve • Reduce viral replication T cell production
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/mm 3 ) • High dose: increased CD4 count by 75% by week 48 (239 403 cells/mm 3 ) • 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
Acknowledgements • Drs. Rupert Kaul and Sharon Walmsley • Rodney Rousseau (Probiotic study graduate student) • Robert Reinhard
Clinical recommendations • Start ART early with emphasis on adherence • Monitor subclinical opportunistic infections (CMV, TB)
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
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?
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
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