2014 towards an hiv cure symposium melbourne
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2014 “Towards an HIV Cure” symposium Melbourne. Impact of HAART on HIV Reservoirs. Pr Christine ROUZIOUX Virologie – Université Paris Descartes.

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2014 towards an hiv cure symposium melbourne

2014 “Towards an HIV Cure” symposiumMelbourne

Impact of HAART on HIV Reservoirs

Pr Christine ROUZIOUX

Virologie – Université Paris Descartes


2014 towards an hiv cure symposium melbourne

  • The objective of this presentation is to understand the extent of which ART can reduce and limit the establishment and the persistence of the HIV reservoirs, as an important step towards HIV cure.

  • There is no consensus on the definition of HIV reservoirs

  • There is no consensus on HIV reservoir markers

  • However, there are many recent results which bring information that could help to design studies, to select patients as good candidates to receive the best combinations aiming at reducing HIV reservoirs and to achieve HIV drug free remission.


Definition of hiv reservoirs

Definition of HIV reservoirs

Culture assay : IUPM

Lewin & Rouzioux, AIDS 2011

Rouzioux & Richman, 2012


2014 towards an hiv cure symposium melbourne

Lewin & Rouzioux, AIDS 2011


2014 towards an hiv cure symposium melbourne

Comparative analysis of measures of viral reservoirs in

HIV eradication studies: Erickson et al , Plos Path, 2013

r=0.70 p=0,008

r=0.65 p=0.016

r=0.58 p=0.015

r= 0.63 p=0.0042


2014 towards an hiv cure symposium melbourne

Kinetics of HIV reservoir decrease

Treatment

Interruption

Viral Rebound

- Naïves

Palmer S et al. J Internal Medicine 2011


Impact of early haart on hiv reservoirs

Impact of Early HAART on HIV Reservoirs

272 Chronic Infections

ADN-VIH (Log / M PBMC)

35 Primary- infections

Better HIV-DNA decrease Better immune restoration

Time with HIV-RNA <50 copies/ml (Years)

Hocqueloux et al , JAC 2013


Impact of art on gut reservoirs

Impact of ART on Gut reservoirs

  • Yukl S et al, AIDS 2010

  • The Distribution of HIV DNA and HIV RNA in Cell Subsets differs in Gut and Blood in patients on HAART. Intensification with raltegravir produced no consistent decrease in HIV-RNA and HIV-DNA in blood, duodenum, colon or rectum. Moreover, ileum support ongoing productive infection, even in patients with plasma HIV-RNA undetectable.

  • Chege D et al AIDS 2012

  • In long term virologically suppressed patients on HAART, intensification with raltegravir did not result in further decay of HIV-DNA in either the blood or GUT after 48 and 96 weeks of therapy.

  • Ananvoranitch J et al, Plos one 2012:

  • Gut T cell depletion and HIV reservoir seeding increases with progression . HAART induced immune restoration and reduced reservoir size

  • Kök A et al, Mucosal Immunology, 2014:

  • Early initiation of HAART helps to preserve and /or restore mucosal gut homeostasis, and reduce the gut reservoirs HIV-DNA level.


Anrs 147 optiprim study design

ANRS 147 OPTIPRIM : Study design

Arm 1 (N=45):

Arm 2 (N=45):

Primary end-point :

HIV-DNA level at M24

Darunavir/R: 800/100 mg QD

+ Tenofovir/emtricitabine:

245/200 mg QD

+ Raltegravir: 400 mg BID

+ Maraviroc: 150 mg BID

Darunavir/R: 800/100 mg QD

+ Tenofovir/emtricitabine:

245/200 mg QD

Co-enrollment:-Cohort CO6 PRIMO

-

VISCONTI ?

Treatment interruption

Inclusion criteria:

Patients with Acute HIV-1 infection < 10weeks

0

M24

M30

Chéret et al , CROI 2014


2014 towards an hiv cure symposium melbourne

ANRS 147 : OPTIPRIM trial : impact on reservoirs

HIV-DNA kinetic from baseline to month 24

A

B

  • HIV-DNA log copies/ per 106 PBMC

  • strongdecrease and continiousslope

B. HIV-DNA log copies per ml of blood

Could we do better?

Chéret et al , CROI 2014


2014 towards an hiv cure symposium melbourne

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher et al PNAS 2014


2014 towards an hiv cure symposium melbourne

Probability to maintain HIV RNA <400 copies/ml after treatment interruption.

: Immunovirological parameter evolution of the two post treatment controller patients

A

C

D

(PTC 1 and 2).


2014 towards an hiv cure symposium melbourne

Impact of 2 years of HAART in acute patients:

OPTIPRIM ANRS147

Chéret et al CROI 2014


Hiv blood reservoirs in t cd4 subsets

HIV bloodreservoirs in T CD4+ subsets

HAART at the Chronic PhaseHAART in Primary infection

Chomont et al, Nat. Med 2009

Chéret et al, 2014 : OPTIPRIM ANRS 147

Elite controllers - VISCONTI Patients


Interactions between activation inflammation and hiv reservoir levels

Interactions between Activation/ Inflammationand HIV reservoir levels

Jain et al JID, 2013


2014 towards an hiv cure symposium melbourne

Interactions between Activation/ Inflammationand HIV reservoir levels

Murray et al J Virol, 2014


Impact of early haart

Impact of early HAART

Murray et al J Virol, 2014


2014 towards an hiv cure symposium melbourne

2013


2014 towards an hiv cure symposium melbourne

The VISCONTI study

OR1

KPV

OCP

CXK

9

9

9

9

10

10

10

10

2000

2000

2000

2000

8

8

8

8

10

10

10

10

14 patients with Remission

7

7

7

7

10

10

10

10

1500

1500

1500

1500

6

6

6

6

10

10

10

10

5

5

5

5

10

10

10

10

CD4+ T cells/mm3

CD4+ T cells/mm3

RNA copies/ml

CD4+ T cells/mm3

1000

1000

1000

1000

4

RNA copies/ml

4

RNA copies/ml

4

RNA copies/ml

4

CD4+ T cells/mm3

10

10

10

10

3

3

3

3

10

10

10

10

2

500

2

500

2

500

500

2

10

10

10

10

1

1

1

1

10

10

10

10

0

0

0

0

0

0

0

0

10

10

10

10

01

02

03

04

05

06

07

08

09

10

11

99

00

01

02

03

04

05

06

07

08

09

02

03

04

05

06

07

08

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10

96

98

00

02

04

06

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10

Year

Year

Year

Year

OR8

LY1

MWP

OR2

9

9

9

10

10

10

9

10

2000

2000

2000

8

8

8

10

10

10

2000

8

7

10

7

7

10

10

10

1500

1500

1500

6

6

7

6

10

10

10

10

1500

5

5

5

10

6

10

10

10

CD4+ T cells/mm3

CD4+ T cells/mm3

CD4+ T cells/mm3

4

RNA copies/ml

1000

1000

4

1000

RNA copies/ml

4

RNA copies/ml

10

10

10

5

10

CD4+ T cells/mm3

RNA copies/ml

1000

3

3

3

10

10

10

4

10

2

2

2

500

500

500

10

10

10

3

10

500

1

1

1

10

10

10

2

0

10

0

0

0

0

0

10

10

10

98

99

00

01

02

03

04

05

06

07

08

09

10

11

99

00

01

02

03

04

05

06

07

08

09

10

01

02

03

04

05

06

07

08

09

10

0

1

10

Year

Year

Year

01

02

03

04

05

06

07

08

09

10

11

Year

GXR

OR3

LY2

JOGA

9

9

9

10

10

10

2000

2000

2000

8

8

8

10

10

10

9

9

10

10

7

7

7

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10

10

8

8

2000

2000

10

10

6

1500

1500

1500

6

6

10

10

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7

7

10

10

5

5

5

10

10

10

CD4+ T cells/mm3

6

6

1500

1500

10

10

CD4+ T cells/mm3

4

RNA copies/ml

4

RNA copies/ml

4

RNA copies/ml

1000

1000

1000

CD4+ T cells/mm3

10

10

10

5

5

10

10

3

3

3

10

10

10

4

4

1000

1000

10

10

2

2

2

500

500

500

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10

10

3

3

10

10

1

1

1

10

10

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2

2

500

500

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08

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00

01

02

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08

09

10

11

0

0

0

0

10

10

Year

Year

Year

SL2

MO1

9

10

2000

8

10

RNA copies/ml

7

CD4+ T cells/mm3

RNA copies/ml

CD4+ T cells/mm3

10

1500

6

10

CD4+ T cells/mm3

RNA copies/ml

5

10

1000

4

10

3

10

500

99

00

01

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08

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Year

Year

10

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0

1

96

98

00

02

04

06

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10

12

Year

Saez-Cirion et al Plos Pathogens 2013


2014 towards an hiv cure symposium melbourne

Post-treatment controllers have

an extremelyweak HIV-1 reservoir

6

5

4

HIV-DNA (log10 copies/106 PBMC)

3

2

1

PHI

Chronic

cART

ALT

HIC

PTC

Lewin and Rouzioux AIDS, 2011


2014 towards an hiv cure symposium melbourne

Post-treatment controllers have low levels of HIV-1 DNA in PBMC, which further decreased after treatment interruption in some cases

4

3

2

Cell associated HIV-1 DNA

(Log copies/106 PBMC)

1

0

0

30

60

90

120

Time after treatment

interruption (months)

Saez-Cirion et al Plos Pathogens 2013


2014 towards an hiv cure symposium melbourne

The VISCONTI patients, now ! (n=20)

Post-treatment interruption

  • Median Follow-up = 9.3 years(IQR: 8.4-10 – range: 4.5-12.5)

  • Median age = 48 (IQR: 43-53)

  • No AIDS event

  • Treatment resumption in 1/20 patient

    • Cancer ORL

    • VL <40 cp/mL before cART resumption

    • In remission after 2 years

  • No treatment resumption linked to viral replication

  • 338 Viral loads measured after treatment interruption

    • 287/338 (85%) were <50 cp/mL

    • 45/338 (13%) were >50 et <400 cp/mL

    • 6/338 (2%) were >400 cp/mL


Conclusions

CONCLUSIONS

  • The study of HIV reservoirs in treated patients bring many new arguments in favor of early treatment initiation:

    • Protecting long-life memory T cells

    • Reducing the damage of activation/inflammation

    • Inducing VISCONTI cases with long-term control after treatment interruption

  • Pharmacological studies indicate that better combinations with better concentrations in lymphoïd tissues, including lymph nodes, might have a better impact on HIV reservoirs.

  • Lastly, the impact of new drugs, new combinations should be systematically evaluated on HIV reservoirs, to prepare patients to the next objective to achieve long-term HIV drug free remission.


2014 towards an hiv cure symposium melbourne

Acknowledgements

Patients and clinicians who participate in the study

Institut Pasteur

Régulation des Infections Rétrovirales

Asier Saez-Cirion

Gianfranco Pancino

Daniel Scott-Algara

Françoise Barré-Sinoussi

Pierre Versmisse

CHU Necker Enfants Malades

Laboratoire de Virologie

Christine Rouzioux

Véronique Avettand-Fenoel

Adeline Mélard

CHU Pitié-Salpetriere

INSERM UMR-S 945

Brigitte Autran

Charline Bacchus

Benjamin Descours

Assia Samri

Ioannis Theodorou

Julien Guergnon

Faculté de Médecine Paris Sud

INSERM U1012

Alain Venet

Olivier Lambotte

Cécile Goujard

Isabelle Girault

Camille Lecuroux

INSERM U1018

Laurence Meyer

Faroudy Boufassa

CHR Orléans La Source

Service Maladies Infectieuses

Thierry Prazuck

Laurent Hocqueloux

INSERM UPMC U943

Dominique Costagliola

Valérie Portard

CHU Hôtel-Dieu

Unité Immuno-Infectiologie

Jean-Paul Viard

FHDH

“French Hospital

Database on HIV”

ANRS CO18

“HIV controllers”

ANRS CO6

“PRIMO”

ANRS CO15

“ALT”


2014 towards an hiv cure symposium melbourne

Merci


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