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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 - - 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
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Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
Clinical Society (year of the guideline release) Therapy success Low Level Viremia Virological Failure DAIG, Deutsche AIDS-Gesellschaft (2017) < 50 cp/ml (within 6 months) 50 – 200 cp/ml < log ↓ after 4 weeks or >50 cp/ml after 6 months >2x >50 cp/ml after suppression DHHS, Department of Health and Human Service (2018) VL < LLOD (<20-75 cp/ml) (within 12-24 weeks) LLOD – 200 cp/ml 2x > 200 cp/ml IAS-USA, International AIDS Society (2018) < 50 cp/ml (within 24 weeks) 50 – 200 cp/ml 2x > 200 cp/ml (after suppression) EACS, European AIDS Clinical Society (2018) < 50 cp/ml (within 6 months) 50 – 500 cp/ml (from 10/2017) 50 – 1000 cp/ml (before 10/2017) 2x > 50 cp/ml (6 month after ART start)
The definition of HIV-1 Low Level Viremia and failure is not consistent
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Immune Control in ART Treated Patients with 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
Possible causes of HIV-1 Low Level Viremia
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Is there a possible marker to predict clinical and immunological outcomes? Where does LLV originate from? Active replication from viral reservoirs?
Rationale of the study and study design
What are the implications of long term LLV?
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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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
- f 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.
Rationale of the study and study design
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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In approx. 30% of LLV patients new therapy associated DRM were identified (NGS) In approx. 27% of the LLV patients drug levels were to low In approx. 55% of the LLV were treated with PI 72% of the LLV patients were infected with HIV-1 subtype B
Characteristics of Patients with HIV-1 Low Level Viremia > The group of LLV patients is heterogeneous
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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Comparison of immunological markers of patients witch HIV-1 blips, LLV, and Viremia
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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Routine immunograms of HIV-1 LLV patients do not differ from those with blips but from those with virologic failure.
Comparison of immunological markers of patients witch HIV-1 blips, LLV, and Viremia
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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L L V T N < 4 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6
to ta l H IV D N A [c p /1 0 6 c e lls ] n s
*** ***
L L V T N < 4 0 1 0 -1 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7
in te g ra te d H IV D N A [c p /1 0 6 c e lls ]]
* *** *
L L V T N < 4 0 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8
2 -L T R c irc le s [c p /1 0 6 c e lls ]] n s n s n s
Transcriptional HIV-1 activity in PBMCs:
L L V T N < 4 0 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4
c o p ie s H IV c e ll R N A [c p /1 0 5 c e lls ]
** ****
n s
Proviral HIV-1 DNA in PBMCs:
HIV-1 proviral DNA loads during LLV are higher than in patients under the LOD
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
LLV might derive from infected transcriptionally active periphery blood cells; active replication
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< 4 0 L L V T N 1 0 -2 1 0 -1 1 0 0 1 0 1 1 0 2
x -fo ld ch a n g e P K R e x p re s sio n
** **
< 4 0 L L V T N 1 0 -2 1 0 -1 1 0 0 1 0 1 1 0 2
x -fo ld c h a n g e IF N b e xp re s sio n
< 4 0 L L V T N 1 0 -2 1 0 -1 1 0 0 1 0 1 1 0 2
x -fo ld ch a n g e O A S 1 e x p re s sio n
Expression levels of IFN stimulated genes (ISGs):
Patients with LLV might have higher ISG expression indicating chronic inflammation
Expression of IFN stimulated genes during LLV is higher than in patients under the LOD
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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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
TTV as a suitable surrogate marker for HIV LLV and disease progression?
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
T N L L V < 4 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7
T T V D N A [c o p ie s /m l p la s m a ]
**
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
n .s. n .s.
L L V < 4 0 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8
T T V D N A [c o p ie s /1 0 *6 c e lls ] n .s .
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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?
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
- Summary
Immune Control in ART Treated Patients with HIV-1 Low Level Viremia
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