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Presentazione delle query: discussione e verifica congruità database ARCA per ciascuna query

This study explores patient characteristics, treatment durability, and outcomes of DRV+3TC vs. ATV+3TC regimens. Recommendations based on long-term efficacy and safety data.

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Presentazione delle query: discussione e verifica congruità database ARCA per ciascuna query

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  1. Presentazione delle query:discussione e verificacongruità database ARCAper ciascuna query Stefano Rusconi Divisione Clinicizzata di Malattie Infettive DIBIC “Luigi Sacco” Università degli Studi Milano ARCA MENTOR SCHOOL, SIENA 06-07. X. 2016

  2. Query Caratteristiche dei pazienti che sono messi in trattamento con terapia a due farmaci DRV+3TC vs. ATV+3TC, analisi di efficacia e durability del trattamento.

  3. Raccomandazioni dalle LG Sean G. Kelly et al., 2016

  4. Studi AtLaS e SALT «Efficacia e sicurezza a lungo termine della semplificazione di una duplice terapia basata su ATV/r e 3TC»

  5. Which patients? what regimens? 1 pill 2 pill

  6. S Nozza et al.

  7. Dual DRV/r & 3TC: OSR + UCSC JAIDS 2016, in press

  8. Treatment discontinuation Virological Failure 1a) 1b) Treatment discontinuation for any cause Treatment discontinuation for adverse events 1c) 1d) Log rank test: p=0.004 Log rank test: p=0.006 JAIDS 2016, in press

  9. ** ** ** * ** ** * ** ** ** ** ** ** * ** * * ** ** * ** ** ** ** ** * * ** * * ** ** * JAIDS 2016, in press

  10. Caratteristiche dei pazienti che sono messi in trattamento con terapia a due farmaci DRV/r+3TC vs. ATV/r+3TC, analisi di efficacia e durability del trattamento.

  11. Query del Gruppo C variabili: • età • sesso • presenza di coinfezione HCV • modalità trasmissione • genotipo storico • AIDS si/no • CD4 e carica virale pre-terapia basale • CD4 e carica virale pre-switch alla dual

  12. numero linee terapeutiche precedenti • fallimenti virologici • regime precedente lo switch • motivo di switch • data inizio HAART • durata soppressione virologica • durata infezione HIV (dalla diagnosi) • lunghezza totale del follow-up sotto i trattamenti in oggetto • Cause di discontinuation • Resistenze al fallimento • assetto immunologico durante il trattamento

  13. Query Frequenza di fallimento della terapia di prima linea basata su INI vs. PI a partire dal 2008 (anno di inizio INI), durability dei due tipi di trattamento e caratteristiche del paziente selezionato per DTG in prima linea (inclusa analisi di efficacia per follow-up possibile ad oggi).

  14. July 2016 Updates on Recommended Regimens for First-line ART 3-drug regimens • DHHS[1] • Recommended regimens include 3 INSTIs and 1 boosted PI • Primary change since Jan 2016 update is addition of TAF/FTC • IAS-USA[2] • All recommended regimens include INSTI + TAF/FTC or ABC/3TC • Major changes since 2014 update include removal of NNRTIs, boosted PIs, and TDF Preferred/recommended 1. DHHS Guidelines. July 2016. 2. Günthard HF, et al. JAMA. 2016;316:191-210.

  15. Doge Antonio, 2016

  16. Frequenza di fallimento della terapia di prima linea basata su INI vs. PI a partire dal 2008 (anno di inizio INI), durability dei due tipi di trattamento e caratteristiche del paziente selezionato per DTG in prima linea (inclusa analisi di efficacia per follow-up possibile ad oggi) Gruppo B

  17. Attività svolte • Criteri di inclusione • Pazienti HIV che iniziano il primo regime terapeutico • Trattati dal 2008 in poi • Trattati solo con INI, ma senza PI né NNRTI • Trattati solo con PI, ma senza INI né NNRTI • Creazione degli script SQL da parte di tutto il gruppo per l’estrazione dei dati secondo i criteri di cui sopra • Spiegazione della struttura base di una query SQL: SELECT, FROM, WHERE, LIKE, AND, OR, YEAR, JOIN, ecc. • Elaborazione del risultato della query • Pazienti trattati con INI: 98 (DTG: 28; RAL: 55; EVG: 15) • Pazienti trattati con PI: 726 (da revisionare tramite esclusione di terapie non triple)

  18. Query Impatto delle mutazioni di resistenza agli NRTI o PI o NNRTI sulla terapia con INI / DTG nel naive con resistenza trasmessa e nel paziente con pregressi fallimenti. Confronto con impatto delle stesse mutazioni sulla terapia con PI (caso-controllo 2:1?).

  19. Hotel Nhow, Milano, 2012 pausa pranzo con Antonio Di Biagio e Andrea De Luca

  20. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8–4·7) for patients in the no TDR group, 4·7% (2·9–7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9–19·0) for those in the TDR and resistant group (log-rank p<0·0001). In stratified analysis, the hazard ratio for the risk of virological failure in patients withTDR who received fully-active cART that included a non-nucleoside reverse transcriptase inhibitor (NNRTI) compared with those without TDR was 2·0 (95% CI 0·9–4·7, p=0·093). L Wittkop et al. Lancet I.D. Volume 11, No. 5, p363–371, May 2011

  21. Query % of RAL virological failures (overall); % RAL virological failures with mutations; % of RAL virological failures without mutations.

  22. INI resistance is uncommon in drug naïve patients • Increased use of INSTI not paralleled by increased INSTI TDR • Only one case in 1316 (0.1%) with T66I but the sample dates back to 2001 • No cases following clinical introduction of INSTI • Likewise, minor INSTI resistance mutations (e.g. 74M, E92G, T97A, E138K, R263K) also do not increase Scherrer, JID 2016

  23. Time trends of INSTI resistance in treatment failing patients • A total of 57 persons with intermediate or high level INI resistance were identified January 2009 to October 2015 • Apparent increase in selection of mutations at integrase codons 66, 140, 148, 155 and 263 • Although the prevalence of INI resistance is increasing, INI resistance remains low in comparison to RT and PI resistance Lepik, CROI 2016

  24. One out of five US patients tested (N=1,764) during the first 3 years of InSTI GRT availability harbored at least one “major” InSTI resistance mutation 1905 sequences analyzed from InSTI GRT, representing 1764 patients in 39 states; 1168 (66%) had paired pol sequences. The number of tests increased over time, from 73 in 2009 to 1097 in 2011 Hurt C et al CROI 2013 #poster 591

  25. One out of five US patients tested (N=1,764) during the first 3 years of InSTI GRT availability harbored at least one “major” InSTI resistance mutation Dolutegravir is likely to be active against most variants observed, however 43% of patients with InSTI resistance (8.7% overall) harbored R263K (n=3) or Q148 + G140 and/or E138 mutations (n=151), conferring up to 20-fold reduced susceptibility to DTG. 1905 sequences analyzed from InSTI GRT, representing 1764 patients in 39 states; 1168 (66%) had paired pol sequences. The number of tests increased over time, from 73 in 2009 to 1097 in 2011 Hurt, et al CROI 2013 #poster 591

  26. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00–6.87) was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96–4.33). Clin Microbiol Infect. 2013 Jan 4. doi: 10.1111/1469-0691.12100.

  27. Figure 1a. Time to first undetectable HIV-RNA by GSS Clin Microbiol Infect. 2013 Jan 4. doi: 10.1111/1469-0691.12100.

  28. Figure 1b. Time to first undetectable HIV-RNA by weighted GSS Clin Microbiol Infect. 2013 Jan 4. doi: 10.1111/1469-0691.12100.

  29. Coronet initiative (a) T Doyle et al. on behalf of the CORONET Study Group, JAC 2015

  30. Coronet initiative (b) T Doyle et al. on behalf of the CORONET Study Group, JAC 2015

  31. Coronet initiative (c) T Doyle et al. on behalf of the CORONET Study Group, JAC 2015

  32. From an internal analysis of ARCA database, 18.4% of patients receiving Raltegravir regimens experienced a virological failure (ARCA internal data from 1,456 patients treatments including INI).A further analysis (Abstract 322 LB OC101, ICAR  2015) conducted on  1,386 pts (INI-naive  298, INI-experienced 1,088) showed overall:- Primary resistance to INI had been uncommon in Italy;- Q148HKR plus G140S or E138K in 1 (0.3%) INI-naïve patient and in 61 (5.6%) INI-experienced patients;- Modest accumulation of resistance at RAL failure (82% without any of the three canonical mutations at codons 143, 148, 155);- Resistance to INI is independent from viral subtype but related to VL at failure.

  33. Virological failures to raltegravir (RAL) in ARCA database Gruppo A AMS 2016

  34. OBIETTIVI PRIMARIO • FALLIMENTI VIROLOGICI A RAL SECONDARI • FALLIMENTI VIROLOGICI CON MUTAZIONI • FALLIMENTI VIROLOGICI SENZA MUTAZIONI

  35. Definizioni • Tutti i pazienti in terapia con RAL basedregimen • Periodo di arruolamento: 01/01/2008-31/12/2015 • Pazienti HIV-1 e HIV-2 naïve, INI naive, INI experienced con età > 18 anni (c.informato) • Periodo di osservazione almeno 24 weeks • Due rilevazioni sopra le 50 copie/mLo una rilevazione >1000 copie/mL • Mancato raggiungimento <50 copie/ml dopo 24 weeks

  36. Gruppo E:Valutazione durability delle terapie HAART di prima linea dal 2010 al 2016

  37. Caratteristiche tecniche: ottenimento dati Dal database ARCA abbiamo selezionato tutti i pazienti con il campo HIV +: 4631 Dal 2010 al 2016 abbiamo selezionato: 1898 Paziente in HAART di prima linea con TDF+FTC o ABC+3TC: 1729 (91%)

  38. I dati che possiamo ottenere

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