Immune Control in ART Treated Patients with HIV-1 Low Level Viremia - PowerPoint PPT Presentation

Immune Control in ART Treated Patients with HIV-1 Low Level Viremia AREVIR-Meeting 2019 - Immune control in immunocompromised patients Marek Widera

Definitions of HIV-1 Persistent Viremia, Low-Level Viremia, blips LLV between >50 and <1000 cp/ml associated with increased risk of VF (Laprise et al. 2013) Viremia between 50 and 1000 cp/ml might predict the risk of subsequent virologic failure (Swenson et al. 2014) HIV-1 LLV >200 cp/ml predictor for VF (Navarro et al. 2016) Folie 2 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

The definition of HIV-1 Low Level Viremia and failure is not consistent Clinical Society Therapy success Low Level Viremia Virological Failure (year of the guideline release) < log ↓ after 4 weeks or DAIG , Deutsche AIDS-Gesellschaft < 50 cp/ml >50 cp/ml after 6 months 50 – 200 cp/ml (2017) (within 6 months) >2x >50 cp/ml after suppression DHHS , Department of Health and VL < LLOD (<20-75 cp/ml) LLOD – 200 cp/ml 2x > 200 cp/ml Human Service (2018) (within 12-24 weeks) IAS-USA , International AIDS Society < 50 cp/ml 2x > 200 cp/ml (2018) 50 – 200 cp/ml (within 24 weeks) (after suppression) 50 – 500 cp/ml (from 10/2017) EACS , European AIDS Clinical Society < 50 cp/ml 2x > 50 cp/ml (2018) (within 6 months) (6 month after ART start) 50 – 1000 cp/ml (before 10/2017) Folie 3 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Possible causes of HIV-1 Low Level Viremia Issues associated with HIV-1 LLV and blips Therapy associated drug resistance mutations (DRMs) Adherence or compliance issues, drug-drug interactions, pharmacogenomics and metabolism High baseline viral load, slow decline periods (>6mo) Co-infections, vaccination Older generation drugs (former PI) Different test systems, inaccuracy of sampling and measurements Very low CD4 levels (AIDS-patients) Cellular reservoir release of defective viruses Folie 4 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Rationale of the study and study design Where does LLV originate from? Active replication from viral reservoirs? What are the implications of long term LLV? Is there a possible marker to predict clinical and immunological outcomes? Folie 5 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Rationale of the study and study design A retrospective data analysis was performed on a treatment history dataset containing parameters from routine diagnostics HIV-positive patients (HIV+) all cART treated at the University Hospital of Essen from January 2006 to December 2018. Detailed molecular analysis of PBMC and plasma samples from HIV-LLV patients. Immunological markers, PBMC proviral DNA loads caRNA, and novel potential surrogate markers. Folie 6 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Characteristics of Patients with HIV-1 Low Level Viremia In approx. 55% of the LLV were treated with PI In approx. 27% of the LLV patients drug levels were to low In approx. 30% of LLV patients new therapy associated DRM were identified (NGS) 72% of the LLV patients were infected with HIV-1 subtype B > The group of LLV patients is heterogeneous Folie 7 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Comparison of immunological markers of patients witch HIV-1 blips, LLV, and Viremia Folie 8 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Comparison of immunological markers of patients witch HIV-1 blips, LLV, and Viremia Routine immunograms of HIV-1 LLV patients do not differ from those with blips but from those with virologic failure. Folie 9 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

HIV-1 proviral DNA loads during LLV are higher than in patients under the LOD Proviral HIV-1 DNA in PBMCs: n s *** * in te g ra te d H IV D N A [c p /1 0 6 c e lls ]] n s * n s n s *** *** 1 0 6 1 0 7 1 0 8 to ta l H IV D N A [c p /1 0 6 c e lls ] 2 -L T R c irc le s [c p /1 0 6 c e lls ]] 1 0 6 1 0 7 1 0 5 1 0 5 1 0 6 1 0 4 1 0 5 1 0 4 1 0 3 1 0 4 1 0 3 1 0 2 1 0 3 1 0 1 1 0 2 1 0 2 1 0 0 1 0 1 1 0 1 1 0 -1 1 0 0 L L V T N < 4 0 L L V T N < 4 0 L L V T N < 4 0 Transcriptional HIV-1 activity in PBMCs: ** n s **** c o p ie s H IV c e ll R N A [c p /1 0 5 c e lls ] 1 0 4 LLV might derive from infected transcriptionally active 1 0 3 periphery blood cells; active replication 1 0 2 1 0 1 1 0 0 L L V T N < 4 0 Folie 10 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Expression of IFN stimulated genes during LLV is higher than in patients under the LOD Expression levels of IFN stimulated genes (ISGs): ** ** x -fo ld ch a n g e O A S 1 e x p re s sio n x -fo ld c h a n g e IF N b e xp re s sio n x -fo ld ch a n g e P K R e x p re s sio n 1 0 2 1 0 2 1 0 2 1 0 1 1 0 1 1 0 1 1 0 0 1 0 0 1 0 0 1 0 -1 1 0 -1 1 0 -1 1 0 -2 1 0 -2 1 0 -2 < 4 0 L L V T N < 4 0 L L V T N < 4 0 L L V T N Patients with LLV might have higher ISG expression indicating chronic inflammation Folie 11 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

TTV as a suitable surrogate marker for HIV LLV and disease progression? Torque teno virus (TTV) Non-enveloped ssDNA virus Family: Anelloviridae Prevalence in the general adult population is approximately 90-100% Establishes a chronic infection without inducing a previously known pathology in healthy individuals TTV viremia appears to be correlated with immune status n .s. ** n .s. n .s . T T V D N A [c o p ie s /m l p la s m a ] 1 0 7 T T V D N A [c o p ie s /1 0 *6 c e lls ] 1 0 8 1 0 6 1 0 7 1 0 5 1 0 6 1 0 4 1 0 5 1 0 4 1 0 3 1 0 3 1 0 2 1 0 2 N V 0 4 L T L L V < 4 0 < L M a n n -W h itn e y te s t; ** p < 0 .0 0 6 8 M e a n w ith in te rq u a rtile ra n g e Folie 12 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Immune Control in ART Treated Patients with HIV-1 Low Level Viremia - Summary The group of LLV patients is heterogeneous (DRMs, adherence, ART-regimen…). Routine immunograms of HIV-LLV patients do not differ from those with blips. Viral reservoir and HIV-1 transcriptional activity in PBMCs from LLV patients were significantly higher than in patients <LOD indicating ongoing viral replication during LLV. Patients with LLV have higher ISG expression when compared to patients with undetectable viral loads indicating chronic inflammation. TTV-DNA levels were higher in LLV-patients when compared to those with undetectable viral load. Limited immunocompetence in LLV patients? TTV as a marker for disease progression or chronic inflammation? Folie 13 Titel Immune Control in ART Treated Patients with HIV-1 Low Level Viremia

Acknowledgements Institute for Virology HIV/HPSTD-Studienambulanz Ulf Dittmer Stefan Esser Barbara Bleekmann Miriam Dirks Bioinformatics and Computational Biophysics, Helene Sertznig University of Duisburg-Essen Olympia Anastasiou Daniel Hoffmann Tyärk Rütten Daniel Habermann Institut für Immunologie und University of Cologne, Virology University Düsseldorf, Virology Genetik, Kaiserslautern Rolf Kaiser Nadine Lübke Jens Verheyen Veronica di Cristanziano Martin Däumer Alexander Thielen NCT02411071 Folie 14 Titel Ethics Committee of the medical faculty of the University Duisburg-Essen (14-6155-BO)