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Pr Christine Katlama University Pierre et Marie Curie Paris VI Pitié-Salpêtriere Hospital, Paris

Antiretroviral Treatment Strategies. Pr Christine Katlama University Pierre et Marie Curie Paris VI Pitié-Salpêtriere Hospital, Paris. EACS Advanced course AIX 2013. ART : A revolution HIV : a chronic disease. 2011 96% < 500 cp 84 % < 50 cp 59% > 500 CD4.

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Pr Christine Katlama University Pierre et Marie Curie Paris VI Pitié-Salpêtriere Hospital, Paris

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  1. AntiretroviralTreatmentStrategies Pr Christine Katlama University Pierre et Marie Curie Paris VI Pitié-Salpêtriere Hospital, Paris EACS Advanced course AIX 2013

  2. ART : A revolution HIV : a chronicdisease 2011 96% < 500 cp 84 % < 50 cp 59% > 500 CD4 ART : a revolution Simple treatmentavailable Tolerabilityimproved Survival quasi normal HIV a chronicdisease

  3. Viral suppression > 90% • Immune restoration • Better ARV drugs • Simplified treatment • Increased survival • Transmission reduced • Persistent reservoir • Persistent replication • Immune activation • Inflammation • Toxicity ART • Acceleratedaging • Long life therapy • Access to ART A success story of research But a story far from being achieved

  4. HIV Pathogenesis

  5. HIV A disease of immune activation and inflammation HIV replication induces immune activation Immune activation induces inflammation immune exhaustion immune suppression Inflammation induced comorbidities Photo JDD

  6. Immune activation and HIV replication HIV-1 infection and replicationmain target: CCR5+ activated CD4+ T-cells HIV infection is deleterious from very early stages Massive CD4+ T-cell depletionin particular mucosal CD4+ T-cells Massive CD4+ T-cell depletionin particular mucosal CD4+ T-cells Anti-HIVImmune responsecellular and humoral Production of HIV proteinsgp120, nef Bacterialtranslocationincluding TLR-ligands Viralreactivationin particular CMV Systemic immune activationAdaptive and Innate Appay et al, J Pathol 08

  7. HIV is a disease with a long term asymptomatic phase. HIV infection is deleterious from very early stages

  8. ART discontinued 15 10 % cumulated events 5 p < 0,0001 ART maintained 0 DC VS 0 24952512 4 1839 1848 8 1441 1434 16 915 931 20 733 754 24 569 601 28 449 490 36 297 310 40 178 184 44 34 41 12 1112 1122 32 375 398 Mois depuis la randomisation Nb patients SMART HIV replicationisassociated to increasedmortalityand morbidity Associated to increased Inflammation IL6 and coagulation markers Ddimers El-Sadr W.,NEJM 2006,

  9. Pathogenesis of HIV HIV Immune activation Inflammation Immune deficit Cardiovascular risk Bone Cognitive disorders HBV/HCV Cancers Immune deficit Accelerated aging Cancers AIDS Cancers HIV is deleterious by immune suppression and activation

  10. Why do weneed to control HIV replication ? • To preventdisease progression for every HIV infectedindividual • To stop transmission betweenindividuals To control HIV pandemics

  11. HPTN 052 : Transmission of HIV Early treatment versus delayed treatment 1763 couples ; ART > 350 vs standard HPTN 052 HIV • 39 cases of transmissions • 28 related to HIV partner - 1 fromimmediateART group - 27 fromdiffered group p= 0.0001 ART reduced by 96% the risk of transmission Opportunistic infections 20 extra-pulmonary TB cases - 1 from the immédiat ART groupe - 19 from differed group Early ART reduces the risk of tuberculosis

  12. Reservoir Residual viremia and immune activation

  13. Plasma viremia HIV reservoir = residual HIV infection Time of ART initiation : a key element in reservoir establishment

  14. HIV reservoirsdiffersfrom patients groups The ANRS Cohorts Lewin and Rouzioux, Review, AIDS 2011 Early Rouzioux, JID 2005 Elite controllers Lambotte 2008 Primary infection Ghosn, JAC 2010 ALT Martinez,JID 2008 ART/PI Hocqueloux 2010

  15. Primary infection and reservoir dynamics • Fiebig I: RNA+, p24̶ -, 3°G ELISA neg • Fiebig II: RNA+, p24+, 3G ELISA neg • Fiebig III: 3rd-gen ELISA+, WB neg • 68 patients :initiating ART in 2 à 3 days post contamination Prior ART Total HIV DNA lower in Fiebig I stage HIV DNA total undetectable in 22/24 (92 %) Fiebig I Total HIV DNA (c/106 PBMC) Integrated ADN VIH (c/106 PBMC) p = 0,0007 p = 0,002 100 000 p =0,01 p = 0,0005 100 000 10 000 10 000 1 000 1 000 100 100 10 10 0 0 Fiebig I (n = 24) Fiebig II (n = 7) Fiebig III (n = 36) Fiebig I (n = 24) Fiebig II (n = 7) Fiebig III (n = 36) Not detectable 53 % 92 % 29 % Ananworanich J, CROI 2013, Abs. 47

  16. Evolution of HIV RNA and HIV DNA in patients following ART initiation Chronicnaive Chronicnaive Chronicexperienced Chronicexperienced Primo Primo Ngo-Giang-Huong et al. AIDS. 15(6):665-673, April 13, 2001.

  17. 127 ART treated patients • Med Duration : 6.5 y • CD4 med : 580 /mm3 • HIV RNA ( taqman)< 50 cp : 100% • CD4/CD8 : 0.8 • HIV RNA us < 1 cp/ml: 37% • CV médiane: 2.6 cp/ml • Correlation between residual HIV RNA and CD4/CD8 and DNA • No association between residual HIV RNA and activation markers • (CRP, IL6, sTNFR1, CD38) 1027 448 J Infect Dis. 2011 Jul;204(1):135-8.

  18. Goals of Antiretroviral Therapy • Reduce HIV-associated morbidity and prolong duration and quality of survival • Restore and preserve immunologic function: > 500 CD4 ; normalize CD4/CD8 • Maximally and durably suppress HIV-1 RNA • Persistently below level of detection (< 20-75 copies/mL, depending on the assay used) • Isolated “blips” not uncommon in successfully treated patients and not thought to predict virologic failure • Prevent HIV transmission • Decrease maximally reservoirs DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.

  19. Antiretroviral therapy -A highly effective therapy - A highly effective prevention …A «  double hit strategy  »

  20. Viral replication has to maximally suppressed Maximal suppression of HIV required to • Prevent disease progression • Decrease immune activation • Prevent resistance Target below detection •  200 cp/ml : clinical and immunological •  50 cp/ml : resistance • Tomorrow : 1 cp ? • Which benefits • on reservoirs and activation ?

  21. Control of viral replication has to be maximal • Populationlevel • Reduced transmission • progressive control and decrease of epidemics • - Decrease in tuberculosis • Longer durability of efficacy of first lines ART • Decrease of global cost of HIV Individual level Health • Stop disease progression • Optimize immune restoration • Prevent resistance • Optimize survival Daily normal life - to have children - Maximal reduction of sexual transmission risk

  22. Universe : Big Bang day 0 13.82 billion years ago When to start antiretroviral therapy ?

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