CHU Necker, Université Paris Descartes, Historical perspective: Primary HIV Infection as a Critical Window of Opportunity Pr Christine ROUZIOUX CHU Necker, Université Paris Descartes, Paris, France Iwould like to thank the organisers

No conflict of interest to declare

The ANRS PRIMO Cohort 2157 inclusions (june 2017) 48% (N=955) of the patients have been treated at inclusion. N=1275 (63,7%) patients traités avant M01

Primary HIV infection Acute : less than 3 month post-infection 10 15 20 days 5 Acute : less than 3 month post-infection Recent : 3 to 6 months Fiebig stages Décalage tempête cytokinique et réponse immunologique L’envahissement viral en primo-infection donne lieu à une activation immunitaire intense et délétère qui se traduit par une tempête cytokinique dont le niveau est prédictif de l’évolution de la maladie ( dont une d’intérêt majeur IP 10 chimioattractive pour les T, monocytes, NK et permettrait une amplification de la réponse anti-VIH), est à l’origine de l’apoptose massive de B et T. La réponse immunologique détectée (anticorps) est alors synchrone de la redistribution massive du virus. La tem^pte cytokinique facilite l’expansion virale et participe à l’expansion des réponses spécifques cellulaires et humorales. CLINICAL SYMPTOMS

Impact of early /late treatment on Total HIV-DNA Chronic Phase Primary Infection - 372 Chronic Patients 25 PHI patients HIV-RNA<50copies/ml - >1200 samples HIV-DNA Immunological benefit significantly better in PHI patients Hocqueloux et al. JAC 2013

Time from treatment initiation Cohort ANRS PRIMO : HIV-DNA decay 327 PHI patients on HAART, 1305 samples, 3 slope mixed model Time from treatment initiation Laanani, CID 2015

Long term outcome of patients after HIV1 primary infection in the ANRS PRIMO cohort Immediate ART Differed ART HIV DNA levels CD4 count CD4:CD8 ratio Dynamics since cART initiation of CD4 count, CD4/CD8 ratio and HIV DNA levels, predicted by a mixed-effects model IAS, Paris Poster S. Novelli et al HIV DNA levels

Long term outcome of patients after HIV1 primary infection in the ANRS PRIMO cohort Immediate ART Differed ART HIV DNA levels CD4 count CD4:CD8 ratio Dynamics since cART initiation of CD4 count, CD4/CD8 ratio and HIV DNA levels, predicted by a mixed-effects model Immediate ART initiation during primary infection is associated with accelerated immune reconstitution and decreased size of viral reservoir. levels of inflammatory markers under cART did not differ according to the timing of cART initiation. Early cART initiation failed to normalize inflammation levels, compared to healthy donors IAS, Paris, Poster S. Novelli et al HIV DNA levels

Integrated HIV DNA in the Gut 40 Impact of HAART on Gut In patients Macaque Model Whitney Nature 2014, Okoye CROI 2014 Ananworanich J, CROI 2013, Abs. 47 10 100 1000 10 000 p = 0,01 Integrated HIV DNA in the Gut (c/106 cellules) S0 S24 4 8 Fiebig I Fiebig III n : Early initiation of HAART has in impact on the lympoid tisssue such as the gut

Impact of HAART on T cell subsets OPTIPRIM ANRS trial Chéret, et al , JAC 2015 PTC Dia à modifier à condenser avec la précédente

Acutely-infected vs PTC patients Acutely-infected patients PTC Dia à modifier à condenser avec la précédente Chéret, et al , JAC 2015 Saez-Cirion, PloS Path, 2013

HIV-DNA in T lymphocyte subsets HAART at the Chronic Phase 24 mths of HAART in PHI ANRS 147 OPTIPRIM trial The distributionof infected cells among the Tcell populationsin blood and tissues is also an important parameter to take in account as it is different among patients especcially in those who have been treated realy or later Chomont et al, Nat. Med 2009 Chéret, Bacchus et al, JAC 2015 Chéret et al, Lancet ID 2015 Considering 2 patients on HAART with the same HIV-DNA level in PBMC - A PHI patient early treated will have a short live reservoir - while a chronic patient will maintain a long-live reservoir

Impact of HAART TCM

Impact of HAART in semen Changes in blood and seminal HIV-RNA and HIV-DNA between D0 (cART initiation) in PHI and M24 (2 years of cART) ANRS-OPTIPRIM trial Chéret et al submitted

Conclusions Definitely, treatment initiation at the time of primary infection is a real opportunity: To block the establishment of the reservoir and to reduce the reservoir size To protect the immune system The best is to start as soon as possible - to increase individual benefits - to reduce the high risk of tHIV ransmission Recommandations to increase acess to HIV Testing, in case of clinical symptoms and/or risk of exposure to HIV infection.

Thanks to Institut Pasteur Régulation des Infections Rétrovirales Asier Saez-Cirion Michaela Muller-Trutwin CHU Necker EA 7327 Paris V Laboratoire de Virologie Véronique Avettand-Fenoel Adeline Mélard Antoine Chéret Jean-Paul Viard CHR Orléans La Source Service Maladies Infectieuses Laurent Hocqueloux Thierry Prazuck CHU Pitié-Salpétrière INSERM UMR-S 945 Brigitte Autran Assia Samri Charline Bacchus INSERM U1018 Laurence Meyer Cécile Goujard Faroudy Boufassa