Should we treat HIV Controllers ?

IAS 2013

Pr Olivier Lambotte

Department of internal medicine and clinical immunology

Bicêtre Hospital, University Paris South

International guidelines for anti-retroviral treatment

• USA (NIH)• ANRS • European AIDS Clinical Society• International AIDS Society= ART is recommended for all HIV-1 infected patientsReasons: - To block viral replication leads to immune reconstitution with CD4

T cell increase- Control of HIV leads to reduced immune activation and its

consequences (immunological and clinical)- To block viral replication leads to reduced HIV transmission

What would be the reasons to treat a HIV controller ?

• HIV controllers can be considered as a model of functional cure ...

What would be the reasons to treat a HIV controller ?

• Viral replication ?• Decrease of the CD4 T cell count ?• Both ?

• What’s about the role of immune activation and chronic inflammation in these patients ?

Viral replication• Viral escape

– A rare event which should question a superinfection (Sajadi et al. JAIDS 2009, Rachinger CID 2008)

– Controllers are able to control burst of viral replication (Rachinger et al)

– On a 4-year period, in the French cohort (220 patients), 5 « viral escapes » with two consecutive VL > 2000 RNA copies/mL

– Only 2 are treated, the 3 others became « viremic controllers »

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Viral replication• The virus

– It can be a reason to treat a controller• BUT viral replication is present in all (?) controllers• There is a low-grade viral replication in all (?) controllers

(range ART-treated patients [1-10 RNA copies/mL]– Hatano et al. (J Virol 2009): longitudinal follow-up 45/46 patients HIC had 1 detectable usVL- CO21 ANRS Codex: first 100 enrolled patients

- 76 4 < usVL < 400- 24 usVL < 4- At 12 months: among the 16 with a sample, only 8 have a

usVL still < 4 RNA copies/mL

The CD4 T cells• The decrease of the CD4 T cell count• In the US Army cohort, the CD4 T cell counts decreased in

6 / 25 controllers (Okulicz et al JID 2009)

• In the French Observatory, two-third of the controllers had a negative slope of their CD4 T cell count

• Loss of 14 [-12 ; -16] CD4/year• In the French ANRS CO21 Cohort:

– At enrollment, the median CD4 T cell count was 752/mm3 [IQR : 540-957]– 10 confirmed « immunological escape » = two consecutive CD4 T

cell counts < 350/mm3– 8 are treated by ART

What is driving the CD4 T cell decrease in Controllers ?

• The virus• Immune activation• Immunosenescence

CD4 T cell decrease is related to HIVPossible role of blips

– 1 blip was associated with a negative slope of CD4 T cell counts in controllers of the French Observatory (Boufassa et al. PLoS One 2011)

The virus is involved in some HIC

Detectable VL in 34/35 samples

What is driving the CD4 T cell decrease in Controllers ?

• The virus– Yes, but not in all patients– Role of blips – Very slow CD4 T cell recovery in 36 HIV controllers

on ART from 4 cohorts

• Immune activation• Immunosenescence

(Sedaghat et al CID 2009)

CD4 T cell decrease is related to immune activation

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Hunt P et al. JID 2008

HIV controllers have higher activation of CD4 and CD8 T cells than HIV-

S Potter J Virol 2007

Correlation between the CD4 T cell count in controllers and CD4 and CD8 T cell activation

(P Hunt JID 2008 )

Immune activation in HIV controllers has several causes

App

ay e

t al.

2008

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Microbial translocation is higher in controllers than in healthy donnors (collaboration ANRS EP36) Brenchley J et al. Nat Med 2006

Microbial translocation is correlated with CD8 T cell activation

Hunt et al JID 2008

A consequence of chronic inflammation: Cardiovascular risk seems to be increased in HIV controllers Hsue P, AIDS 2009

AIDS 2012

Consequences of immune activation seem to be present in HIV Controllers

What is driving the CD4 T cell decrease in Controllers ?

• The virus• Immune activation

– Microbial translocation– Anti-HIV immune response– Other unknown mechanisms

• Immunosenescence– Decreased lymphopoiesis in controllers with low

CD4 T cell counts (Sauce et al. Blood 2011)

• But real life is not simple …

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Spontaneous fluctuations of CD4 T cell counts are common in HIV controllersEven with periods below 500 /mm3, with or without a clear relation with viral blips

Should we treat HIV controllers ?

• Two major points – It is not an emergency– The patient’s opinion is essential > observance

• If the CD4 T cell decrease is significant and durable with/without viral replication : YES with ART

• If the CD4 T cell count is stable without blips: NO (situation of functional cure ?)

• In the other situations...

Should we treat HIV controllers ?• Two major points

– It is not an emergency– The patient’s opinion is essential > observance

• In the other situations:• To target immune activation is a major goal and a

suject of research : Combination of hydroxychloroquine, statine, low dose steroids, etc... WITH ART

• We need markers which could help the clinician – Markers of immune activation on CD4 / CD8 T cells– Biomarkers of inflammation – Viral DNA, us RNA...

INSERM U1012Olivier LambotteCamille LécurouxIsabelle GiraultStéphane HuaChristine BourgeoisAlain VenetSandie GérardNicolas Noel

INSERM U1018Faroudy BoufassaLaurence Meyer

CHU BicêtreCécile GoujardJean-François DelfraissyKatia Bourdic

Institut PasteurAsier Saez-CirionGianfranco Pancino

USAPeter HuntFlorencia Pereyra

CHU NeckerChristine Rouzioux

Patients and clinicians !!

Cohorte ANRS CO21

Profil transcriptionnel des infections par le SIV pathogènes et non pathogènes

Manches et al. JCI 2009

Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV

Infection

(Murray et al. J Virol 2010)