Traitement antirétroviral précoce

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1 Traitement antirétroviral précoce
HIV Cure Research Training Curriculum (CUREiculum) Traitement antirétroviral (ART) précoce, module préparé par : Dr. Jintanat Ananworanich, U.S. Military HIV Research Program (MHRP) with input from Sidaction team (France) Jeffrey Taylor, Collaboratory of AIDS Researchers for Eradication (CARE) Le programme de formation HIV cure est un projet collaboratif visant à rendre accessible la recherche sur la guérison du VIH pour la communauté de la lutte contre le VIH/sida Module contributors: Scientific leads: Dr. Jintanat Ananworanich, U.S. MHRP with input from Sidaction (Serawit Brunk-Landais), France Community leads: Jeffrey Taylor, Co-Chair of the Collaboratory of AIDS Researchers for Eradication (CARE) Community Advisory Board

2 Pourquoi le traitement précoce est-il important ?
Un des moyens les plus efficaces pour limiter le réservoir VIH, préserver l’immunité et réduire l’activation immunitaire. Optimise la réponse aux interventions sur le système immunitaire qui visent à la rémission du VIH. Essentiel pour prévenir la transmission sexuelle du VIH durant la phase aiguë de l’infection. Potentiellement une étape cruciale dans la recherche pour une guérison du VIH. Here are some reasons why early ART is an important HIV cure research strategy: It is one of the most effective ways to contain the HIV reservoir, preserve immunity and reduce immune activation It may optimizing responses to immune-based interventions aimed at achieving HIV remission It is essential to prevent sexual transmission of HIV during acute infection It may be a critical step in clinical research towards an HIV (may lead to a functional cure) It can be done in both resource-rich and resource-limited settings

3 Persistance du VIH Mort cellulaire Cellule au repos
Explain the figure: Cells infected with HIV are generally activated and the majority end in cell death. A minor population of infected cell reverts back to a resting state and can persist indefinitely without being detected by the immune system or antiretroviral therapy.

4 Eliminer les cellules infectées
Strategies pour éliminer la persistance du VIH Vaccin Aigüe Infection VIH ART ARN VIH “Shock and Kill” Eliminer les cellules infectées Avant L’infection VIH Chronique Infection VIH Charge virale Supprimée Interventions possible : Agents anti-latence Anticorps neutralisants à large spectre Thérapie génique There are multiple strategies being investigated to eliminate HIV persistence. This figure shows these strategies along the HIV infection and disease pathway: HIV prevention method such as condoms, pre-exposure prophylaxis or other modality could help prevent HIV. Next, we see acute HIV infection. Some people may be symptomatic (e.g. flu-like syndrome). The acute phase of infection is followed by chronic infection. Individuals who take antiretroviral drugs become virally suppressed. There HIV cure research strategies that are being investigated in those individuals include: latency-reversing agents, broadly-neutralizing antibody and gene-editing therapy. These different strategies are covered in the other modules.

5 Quand s’établie la latence du VIH ?
La latence du VIH (ou persistance) s’établit précocement dans la phase aigüe de l’infection VIH dans toutes les sous-populations de cellules T CD4 Le génome du VIH est intégré silencieusement dans ces cellules, il ne s’exprime pas Un petit nombre de cellules dans lequel le VIH est intégré et latent (y compris les centrales et transitionelles mémoires) persiste indéfiniment et n’est pas ciblé par les ARV et le système immunitaire La persistance du VIH est la barrière principale à la guérison du VIH Scientists have been trying to determine when HIV latency is established. We now know that HIV latency (or persistence( is established very early, almost immediately after HIV infection, in the acute phase in all CD4+ T cell subsets. These cells harbor the viral genome of HIV, which has become integrated inside the DNA but it remains transcriptionally silent (resting state). There is a small number of latent or resting HIV infected cells that persist indefinitely. These cells are not eliminated by ARV drugs or by the immune system. HIV is integrated inside the genome of infected persons. This latency of HIV is the main barrier to finding a cure.

6 Quand s’établie la latence ?
La latence du VIH s’établit dès la phase aiguë de l’infection La latence persiste malgré un traitement précoce et sur le long terme Le pool de cellules infectées de manière latente est peu ou pas détruit en présence d’ARV sur le long terme When is HIV latency established? Here is one of the first papers that showed that HIV is established during the acute phase of infection. HIV latency continues even though people take antiretroviral drugs – either in the early phase or in the long-term. This “pool” of latently infected cells is relatively stable and does not disappear quickly (does not decay) with the continued use of antiretroviral drugs. Archin N et al. PNAS, 2011

7 Quand s’établie la latence ?
L’établissement des réservoirs de SIV chez les singes se fait en moins de 3 jours après l’infection Un traitement initié 3 jours après l’infection chez les macaques bloque l’apparition de virémie dans les PBMC (ARN-VIH et ADN-VIH), mais pas dans les tissus où l’ADN-VIH est déjà détectable Le traitement précoce initié à 3, 7 ou 10 jours post-infection réduit la taille des réservoirs, mais n’empêche pas leur établissement Chez tous les singes (même traités à 3 jours post-infection) il y a eu un rebond viral après l’arrêt des traitements When is HIV latency established? This letter from Nature reports the results of a study done in non-human primates (rhesus monkeys) with the Simian Immuno-Deficiency Virus (SIV). The study showed that the SIV reservoirs become seeded (established) as early as three days after SIV infection. Early treatment reduces the viral load in the peripheral blood mononuclear cells (PBMCs) but the proviral DNA (integrated HIV genome) can also be detected. Early treatment can reduce the size of the viral reservoirs but do not prevent the establishment of those viral reservoirs. When treatment was interrupted, the animals stopped being virally suppressed and rebounded. But it is important to note that the establishment of the SIV reservoir may differ in NHPs as they lack certain host restriction factors. The virus strain, dose and route used to infect the animals may promote viral spread and latency. Whitney JB et al. Nature, 2014

8 Définition des stades de Fiebig ?
107 106 105 104 Phase d’éclipse 103 Virus concentration in extracellular fluid of plasma (copies per ml) 102 Limit of detection of assay for Plasma viral RNA 101 T0 100 10-1 Infection initiale The next fourslides show the acute phase of HIV infection using the Fiebig stages. Dr. Fiebig came up with these stages in an seminal article published in the AIDS journal in 2003.  First, there is the eclipse phase, when it is come which corresponds to the time between infection and the first detection of viral RNA in the plasma.  Fiebig stage I appears in the first 10 – 15 days and is marked by an increase of virus (or viral load). 10-2 10-3 10-4 10-5 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from McMichael AJ, Nature Reviews Immunology, 2010

9 Définition des stades de Fiebig ?
Stade II 107 106 105 104 103 Virus concentration in extracellular fluid of plasma (copies per ml) 102 Limit of detection of assay for Plasma viral RNA 101 T0 100 10-1 Infection initiale The next four slides show the acute phase of HIV infection using the Fiebig stages.  Fiebig stage II corresponds to the first 15 – 20 days. The viral load continues to increase. 10-2 10-3 10-4 10-5 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from McMichael AJ, Nature Reviews Immunology, 2010

10 Définition des stades de Fiebig ?
Stade III 107 106 105 104 103 Virus concentration in extracellular fluid of plasma (copies per ml) 102 Limit of detection of assay for Plasma viral RNA 101 T0 100 10-1 Infection initiale The next four slides show the acute phase of HIV infection using the Fiebig stages.  Fiebig stage III corresponds to the first 20 – 25 days. The viral load starts to stabilize. Symptoms also start to appear at around that time. 10-2 10-3 10-4 10-5 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from McMichael AJ, Nature Reviews Immunology, 2010

11 Définition des stades de Fiebig ?
Stade IIII 107 106 105 104 103 Virus concentration in extracellular fluid of plasma (copies per ml) 102 Limit of detection of assay for Plasma viral RNA 101 T0 100 10-1 Infection initiale The next four slides show the acute phase of HIV infection using the Fiebig stages.  Fiebig stage III corresponds to the first 25 – 30 days. The viral load starts to slowly decrease until it reaches the viral setpoint. 10-2 10-3 10-4 10-5 Reservoir Established ? 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from McMichael AJ, Nature Reviews Immunology, 2010

12 Définition des stades de Fiebig ?
107 Début des symptômes 106 105 104 103 Phase d’éclipse Virus concentration in extracellular fluid of plasma (copies per ml) 102 Limit of detection of assay for Plasma viral RNA 101 T0 100 10-1 10-2 10-3 Etablissement des réservoirs 10-4 This curve may be familiar to you. It is the curve of the viral load present in the blood in the early phase of HIV infection. As you can see, the HIV reservoir is established very early. 10-5 5 10 15 20 25 30 35 40 45 50 70 80 90 100 Days following HIV-1 Transmission Adapted from McMichael AJ, Nature Reviews Immunology, 2010

13 Définition des stades de Fiebig ?
ARN Antigène P24 Specific EIA Présence possible de l’antigène P24 Present on Western Blot Y Plasma Viral RNA (copies per ml) Y Y This is another representation of the Fiebig stages. This time, we show the tests that are able to detect the infection. Stage 1: Only HIV RNA Stage 2: HIV RNA and p24 antigen Stage 3: HVI RNA, p24 antigen and specific enzyme immuno-assay (EIA) Stage 4: The HIV infection starts to appear on the Western Blot Days following HIV-1 Transmission

14 Définition des stades de Fiebig ?
RNA P24 Antigen Specific EIA Possible presence of P24 Antigen Present on Western Blot Y STADE 3 STADE 4 Y Y Here is another way to look at the Fiebig stages: Stage 1: Only HIV RNA Stage 2: HIV RNA and p24 antigen Stage 3: HVI RNA, p24 antigen and specific enzyme immuno-assay (EIA) Stage 4: The HIV infection starts to appear on the Western Blot

15 Traitement précoce = petit réservoir ?
Points clés : 1 Traiter plus tôt = réduire la taille du réservoir 2 Le bénéfice du traitement précoce est maximum lorsque le traitement est initié dans les premières semaines après l’infection Scientists have been able to determine that earlier antiretroviral treatment results in a smaller reservoir size. Also, the benefits of early HIV treatment are maximal when the treatment is started during the first few weeks of infection. But again, early treatment does not prevent the establishment of the HIV reservoir. The various subsets of latently infected cells may persist indefinitely. 3 Mais les sous-populations de cellules infectées de manière latente peuvent persister indéfiniment

16 Que mesure-t-on avec le taux d’ADN-VIH global ?
ADN-VIH intégré ADN-VIH Total Virus capable de se répliquer When we measure the total integrated HIV DNA, we need to remember that there are a lot of defective provirus. The total HIV RNA (dark blue) is not a true reflection of the size of the HIV reservoir that has the potential to replicate. The yellow triangle shows the level of replication-competent provirus. Grand Petit Très petit Ho YC et al. Cell, 2014

17 Qu’entendons-nous par réservoir VIH ?
ADN-VIH Antigènes du VIH (protéine) Here is another way to look at the HIV reservoir. The HIV DNA corresponds to the large reverse triangle (dark blue). The HIV antigen is the small reverse triangle (green). The quantitative viral outgrowth assay (QVOA) can measure the size of the replication-competent virus, but is only a minimal estimate of the actual size of the HIV reservoir. The part in pink corresponds to the likely size of the “real” reservoir. For more information about measuring the HIV reservoir, we invite you to consult the reservoir module as part of this curriculum. QVOA Growing Virus Le vrai réservoir Slide credit: Margolis DM, 2014

18 “Cellule souche” mémoires
Effet du traitement précoce sur l’établissement du réservoir dans les sous-populations de cellules T CD4+ “Cellule souche” mémoires Centrales mémoires Transitionelles mémoires Naïve Effectrices mémoires Différenciées Central Memory = Ideal Reservoir Low frequency associated with lack of disease progression (LTNP) Transitional Memory We know that early antiretroviral treatment can also the distribution of the reservoir in CD4+ T cell subjects. This slide shows the progression of the T cells from naïve, stem cell, central, transitional and effector memory, and finally, terminally differentiated. The central memory cells are the ideal reservoir. People knows as long-term non-progressors (LTNP) have fewer central memory cells. Effector memory cells, in turn, can support residual levels of viral replication with antiretroviral treatment. Effector Memory May support residual levels of viral replication with ART

19 Effet du traitement précoce sur l’établissement du réservoir dans les sous-populations de cellules T CD4+ The size and composition of the latent HIV reservoir is affected by early ART: A: Subsets of CD4 T cells can be identified based on the levels of expression of several cellular markers including CD45RA, CCR7, CD27 and CD95. The pathway of T cell differentiation, i.e. the sequence of development of the different T cell subsets, remains elusive in humans, and it is unclear if the differentiation pathway is linear or branched, one-way or reversible. B. In chronically infected subjects, the contribution of TCM cells to the overall pool of infected cells is important (30). As these cells are long lived, they survive after years of ART and represent the major latent HIV reservoir in subjects who started ART during chronic infection. The contribution of TSCM cells also increases with time. Subjects with acute or recent infection display a small size of the reservoir (as depicted by a reduced size of the grey box). In addition, their TCM cells may be relatively preserved from infection, with a greater contribution of short-lived cells. After years of ART, this may result in a reservoir of a very small magnitude. Ananworanich J et al. Curr Opin HIV/AIDS, 2015

20 Traitement précoce et réservoir dans les sous-populations de cellules T CD4+
Points clés : 1 Les réservoirs semblent être l’obstacle majeur pour la guérison du VIH 2 L’initiation d’un traitement durant la primo-infection préserve les cellules T centrales mémoires 3 Lorsque le traitement est initié en primo-infection, ce sont les cellules T transitionelles mémoires (durée de vie courte) qui forment le réservoir 4 Les traitements limitent la persistance du VIH dans toutes les sous-population de cellules T CD4+ T (Chomont) 5 Les cellules T CD4+ au repos sont de plusieurs types avec différentes propriétés fonctionelles et phénotypique Scientists have also demonstrated that early treatment can change the distribution of the reservoir in the various CD4+ T cell subjects: The long-lived viral reservoir may be the biggest obstacle to cure. When patients are treated during primary infection, the central memory T cells are preserved. When patients are treated during primary infection, transitional memory T cells (with short half-life) contribute most to the reservoir. Early ART limits the persistence of the HIV reservoir in all CD4+ T cell subsets (Nicolas Chomont). Resting CD4+ T cells also have different functional and phenotypic properties, so they may support latency through different mechanisms. There can also be some variability between patients. 6 Elles peuvent dons avoir différents mécanismes de latence 7 Des variabilités inter-patients existent

21 Traitement initié tôt et pris sur le long terme : clé pour des faibles réservoirs VIH et un nombre de T CD4 normal Hocqueloux L et al. JAC, 2013 Figure 1. Bi-exponential model of HIV DNA decay stratified by the timing of treatment initiation. The grey dots represent patients who started treatment during CHI and the triangles represent patients who started treatment during PHI. The grey curve models HIV DNA decay in the CHI group and the black curve models HIV DNA decay in the PHI group. The dotted and dashed lines represent the slopes of decay during the two periods distinguished by the mixed-effects bi-exponential model for the PHI and CHI groups, respectively. From: Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. Hocqueloux L1, Avettand-Fènoël V, Jacquot S, Prazuck T, Legac E, Mélard A, Niang M, Mille C, Le Moal G, Viard JP, Rouzioux C; AC32 (Coordinated Action on HIV Reservoirs) of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS). Author information Abstract OBJECTIVES: To characterize viro-immunological outcomes following long-term combined antiretroviral therapy (cART) initiated during primary HIV infection (PHI) or chronic HIV infection (CHI) and to identify factors predictive of optimal viro-immunological responder (OVIR) status. METHODS: This was a prospective, single-centre cohort study of HIV-1-infected patients on effective cART. Total cell-associated HIV DNA levels and T cell counts before and during treatment were used to identify factors predictive of OVIR status {i.e. low HIV DNA level [<2.3 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs)], together with normalization of the absolute/relative CD4+ T cell counts and CD4+/CD8+ ratio}. RESULTS: A total of 307 patients were enrolled, of whom 35 started cART during PHI (<4 months post-infection) and 272 during CHI. HIV DNA decay was modelled with a non-linear mixed-effects model that showed two phases of HIV DNA decay, both of which were significantly more pronounced in the PHI group. At the end of follow-up, after a median of 4 years of viral suppression (<50 copies/mL), HIV DNA levels were lower in the PHI group than in the CHI group (median = 2.15 versus 2.84 log10 copies/10(6) PBMCs; P< ). Immune reconstitution was more rapid and sustained in the PHI group (median = 883 versus 619 CD4+ cells/mm(3); 41% versus 31% CD4+; CD4+/CD versus 0.77; all P< ). Finally, OVIR status was obtained in 19/35 (54%) and 7/272 (3%) patients in the PHI and CHI groups (P< ), respectively. In a logistic regression analysis, cART initiation during PHI (OR = 16, 95% CI = ) and HIV DNA level <3.3 log10 before treatment (OR = 4.8, 95% CI = ) were independently predictive of OVIR status. CONCLUSIONS: Initiating cART during PHI represents a major opportunity to reduce HIV reservoirs and achieve optimal immune reconstitution. Patients traités en primo infection Patients traités en phase chronique

22 Etude clinique pivot pour le traitement précoce
Actualités des études Thai : RV254/SEARCH010: Le traitement précoce limite la persistance du VIH dans les sous-population de T CD4+ à longue durée de vie La majorité des patiens sont inclus en Fiebig I et III Un traitement très précoce protège toutes les sous-populations de T CD4+ mémoire de l’infection, y compris celles avec une longue durée de vie Le traitement ARV initié en Fiebig I est associé à une préserv ation des fonctions des cellules Th17 dans l’intestin ; cependant, les marqueurs plasmatiques de déterrioration de la barrière intestinale et de la translocation microbienne persistent Now, we turn to pivotal studies involving early antiretroviral treatment. The RV254/SEARCH010 study in Thailand, implemented by the U.S. Military HIV Research Program (MHRP) showed that early ART limits the persistence of the HIV reservoir in long-lived CD4+ T cells subsets: Most participants were enrolled at Fiebig I and III. Very early ART protected all memory CD4+ T cell subjects from infection, including long-lived central memory T cells. ART in Fiebig I was associated with the preservation of poly-functional gut Th16 cells; however, elevated plasma biomarkers of gut repair and microbial translation persisted.

23 Le traitement précoce limite la persistance des réservoirs du VIH dans les sous-populations de T CD4+ à longue durée de vie (RV254/SEARCH010) 0% 63% Stade de l’initiation du traitement 100% Fiebig I Chronic This slide showed that early treatment reduced the size of integrated HIV RNA in long-lived central memory CD4+ T cells. ≤2 weeks = Fiebig I 2 – 4 weeks = Fiebig III ≥24 weeks = chronic Cellules T CD4+ mémoire, à longue durée de vie Nicolas Chomont Updated from Ananworanich J, 2013 CROI

24 Post-treatment control present at sustained remission
Viro-Immunological Sustained CONtrol after Treatment Interruption  VISCONTI Another important study is the VISCONTI cohort in France. VISCONTI stands for Viro-Immunological Sustained CONtrol after Treatment Interruption. This is the group of patients who were treated early during HIV infection, then stopped taking antiretroviral treatment and were able to maintain virally suppressed. Here, we describe an example of post-treatment control. Sáez-Cirion et al. PLoS Pathogens, 2013

25 Cohorte VISCONTI Contrôle durable du VIH après arrêt du traitement qui avait été initié en primo infection Différents des HIV controllers (contrôle du VIH sans jamais avoir pris de traitement) Traitement pris dans les 2 premiers mois de l’infection Contrôle de la virémie sans traitement depuis plus de 9 ans La majorité des VISCONTI n’ont pas d’allèles HLA de classe I protectrices (mais une plus grande proportion d’allèles à risque élevé) et une faible réponse T CD8 (pas de profile génétique favorable) Un faible niveau d’ADN-VIH et le temps court d’initiation du traitement après le début de l’infection sont les points communs des post-treatment control (PTC) Le mécanisme de controle viral est différent chez les PTC et les HIV controllers Des recherches sont en cours pour comprendre les mécanismes de contrôle Key findings from the VISCONTI cohort patients to date include: Durable control of HIV infection after treatment interruption initiated during primary infection (treated within the first 2 months of infection). These patients are different from HIV controllers. In fact, natural viral controllers never received treatment. Most of the VISCONTI cohort patients had not protective HLA alleles. They also had weak CD8+ T cell responses, so their genetic profile was in fact not favorable to fight the infection. VISCONTI cohort patients were able to control viremia without ART for more than 9 years. This is because they had low HIV DNA levels. But we also need more research to better understand the mechanism of viral control. Sáez-Cirion et al. PLoS Pathogens, 2013

26 Etudes pédiatriques : une forme de traitement précoce
Pediatric studies also correspond to a form of early ART. Here, we want neonates to be treated as soon as possible from birth to prevent the establishment and the size of the HIV reservoir.

27 Etudes pédiatriques : une forme de traitement précoce
Bébé du Mississippi Initiation du traitement à moins de 2 jours de vie, sous traitement pendant 18 mois et resté sans traitement et avec un contrôle du VIH pendant 27 mois Une rémission transitoire, mais encourageante Des avancées remarquables : Ré-affirme le fait que le VIH peut persister de manière latente Le traitement précoce peut retarder le rebond de la charge virale Montre que les tests actuels de mesure du réservoir VIH ne sont pas assez sensibles Montre qu’un petit nombre de cellules infectées de manière latente peut raviver l’infection The Mississippi Child is probably the most famous case. We learned a lot from this case. The child started ART at <2 days of life and remained on ART for 18 months. The child was able to remains suppressed for 27 months without ART. This was an encouraging progress for the child, since the Mississippi child: Re-affirmed the concept that HIV could persist in latent HIV reservoirs Provided evidence that early ART could prolong the time to viral load rebound Showed that the current HIV reservoir tests may not be sensitive enough, particularly for infants (lower blood volumes) And showed that only a small number of latently infected cells could rekindle HIV infection and underscored the importance of immune-based therapies as part of a cure armamentarium

28 VIH détecté dans le sang à 2 temps différents
Bébé du Mississippi : chronologie des évènements Naissance 30 heures 18 mois 23 mois 46 mois Rémission de 27 mois Début des ARV Arrêt des ARV Pas de VIH détecté dans le sang This is the timeline of events for the Mississippi child: The only known case of long-term HIV remission in a child The child was born to an HIV-infected mother who was unaware of her HIV status before giving birth Within 24 hours of birth, the infant tested positive for HIV by two different tests The doctor immediately began treating this child with 3 antiretroviral drugs The child received antiretroviral therapy for the first 18 months of life At 18 months, ART was stopped against medical advice and the child missed several clinic visits When the child returned to the clinic at 23 months, doctors and researchers were unable to find HIV in the child’s blood Multiple blood tests over the next two years were unable to detect HIV HIV was detected in the child’s blood 28 months after stopping ART and ART was re-started VIH détecté dans le sang à 2 temps différents VIH détecté dans le sang Persaud D et al. NEJM, 2013 Persaud et al. IAS 2014

29 Considération éthiques et sociales
1 Est-ce que tôt est “assez tôt” ? 2 Traiter tôt ne permettra pas une “guérison” (les adultes ne seront pas guéris parce qu’ils prennent un traitement précoce; risque de malentendus) 3 Les interruptions de traitement ne sont pas médicalement recommandées (études cliniques contrôlées et standardisées; monitorage fréquent) Now, we turn to the ethical, social and implementation considerations for early ART studies. Can you name a few ethical and social considerations of treating individuals in the early phase of HIV infection? For example: How early is “early enough”? Early antiretroviral treatment will not be curative, so we need to be careful about the language used at all times. There is a risk of curative misconception. Treatment interruptions are not medically recommended. For early ART studies, these need to be standardized and closely controlled and monitored. We must also consider whether early ART patients are considered “vulnerable” or “healthy” and what the social perceptions are vs. the actual medical vulnerability and risk of HIV transmission to sexual partners during the acute phase of HIV infection (when viral load is high). There may also be potential impacts (both positive or negative) on interpersonal relationships of being in an early ART study (e.g. early diagnosis, resilience, efficacy towards study involvement, etc). Treatment interruption may also be a problem for HIV transmission. 4 L’interruption de traitement peut être un problème pour la transmission du VIH 5 Impact potentiel (positif ou négatif) sur les relations interpersonnelles

30 Les défis de l’implémentation
Difficile de comparer les études (variabilité du temps d’initiaition des ARV et dans la mesure du reservoir) Recrutement et temps d’initiation du traitement ARV Evolution globale de la recherche “HIV cure” Difficile d’identifier les patients en primo-infection Nature stochastique du rebond viral étant donné la variabilité entre patients There are also obvious implementation challenges for early ART studies Can you think of some? For example: It is difficult to identify people in the acute phase of HIV infection. Thus, recruitment efforts take a long time. Most studies have been small due to date, although the OPTIPRIM study (Lancet ID) includes 90 patients. Scientists also need to determine the best time point to initiative antiretroviral treatment. At this time, it is difficult to compare studies of early ART, because scientists have used different timing of ART initiation and ways to measure the reservoir. There is some variability between how patients respond to early ART. There are also concerns around scalability of this HIV cure research method on a global scale, due to the difficulty of identifying patients in the early phase of infection. 4-week window when HIV IgG AB not yet detected by standard assays Diagnosis of AHI requires NAT (costly) Patients consult physicians at the time of symptoms (e.g. Fiebig stages III – V) (Hocqueloux JAC, 2013).

31 Conclusions et points clés
Le traitement précoce (primo-infection) peut limiter la taille du réservoir VIH Le traitement pris très tôt (Fiebig I) peut influer sur les populations de T CD4+ mémoire infectés (plus courte durée de vie) La persistance du VIH s’établit précocément, dès la phase aigüe de l’infection et persiste indéfiniment Conclusions and key points: ART started during acute HIV infection can limit the size of the HIV reservoir Treatment in the earliest AHI (Fiebig I) may skew distribution of latently infected cells to shorter lived memory CD4+ T cells HIV persistence established early in AHI in memory CD4+ T cells and can persist indefinitely ART in AHI may be the first critical step in clinical research aimed at HIV cure/remission (so HIV+ individuals who take part in early ART studies may be candidates for other HIV cure research strategies at a later time in their HIV infection due to their smaller reservoir size) L’initiation précoce de traitement semble être une première étape centrale dans le cadre de la recherche clinique pour la rémission / guérison du VIH

32 Collaborateurs pour ce module
We would like to thank all the module collaborators: U.S. Military HIV Research Program (MHRP) and the Henry M. Jackson Foundation Collaboratory of AIDS Researchers for Eradication (CARE) and CARE Community Advisory Board (CAB) Sidaction Johns Hopkins Children’s Center and the Johns Hopkins Center for AIDS Research AVAC