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Nnrtis Protease Other Classes STR Clinical and Therapeutic aspects of HIV Sabine Kinloch, MD Royal Free Hospital UCL partners University College Medical School London, UK ISHEID 2014 Conflict of interest Travel grants from Gilead and BMS European Union research grant AMFAR grant Acknowledgments The ISHEID speakers for kindly providing their slides Summary - Unable to cover all presentations - ART 2014: state of art, potency, resistance drug development pipeline - Eradication paradigm ART 2014 - Multiple compounds available-LT toxicity- adherence-aging population-comorbidities-R - Newer compounds - Robust pipeline of new drugs (all classes) - Potency and resistance revisited - Gene therapy - Eradication ART 2014 - Co-morbidities: choice of ART, CV, diabetes, bone, kidney - Long-term treatment with aim of (no) or two development of resistance, decrease of side-effects (short and long-term) - LT Adherence: new ART strategies and drugs - ART for resource-limited countries, children/adolescents - Effect of ART on the epidemic ………….and costs and ……generics ART 2014 - Multiple compounds available - Exciting pipeline - Long-term toxicity - Adherence: treatment for decades - Ageing population - Comorbidities Available Antiretrovirals 2014= 25 NRTIs NNRTIs Protease Other Classes STR Abacavir Efavirenz Inhibitors Didanosine Nevirapine Atazanavir Fusion Atripla Emtricitabine Etravirine Darunavir inhibitors Eviplera Lamivudine Rilpivirine Fos-Amprenavir • Enfuvirtide Stavudine Indinavir R5 Inhibitors Stribild Tenofovir Lopinavir • Maraviroc Zidovudine Nelfinavir Integrase Ritonavir Inhibitors Saquinavir • Raltegravir Tipranavir • Elvitegravir • Dolutegravir …a potent armamentarium PI DTG† RPV LPV/r 22 NNRTI FLAMINGO 19 2 16 4,5 - 15 21 INSTI STAR UpECHO to 90% of treatment-naive patients THRIVE SPRING can now achieve undetectable HIVCASTLE, -1 STARTMRK1 RNAACTG1 -520216 13 ATADAR8 RAL EFV ATV/r DRV/r 10 14 2NN ATV/c** Study Study 103 NVP *EFV/FTC/TDF is not licensed for use in antiretroviral naive patients Large head to head study in Europe17,18 EVG/c ** ATV/c is not yet licensed for use in HIV-infected patients in Europe Small head to head study †DTG is not licensed for use in HIV-infected patients in Europe Adapted from: 1. Lennox JL, et al. Lancet 2009;374:796−806. 2. Riddler SA, et al. N Engl J Med 2008;358:2095–106. 3. Sierra-Madero J, et al. JAIDS 2010;53:582–8. 4. Molina J-M, et al. Lancet 2008;372:646–55. 5. Molina J-M, et al. JAIDS 2010;53:323–32. 6. Ortiz R, et al. AIDS 2008;22:1389–97. 7. Mills AM, et al. AIDS 2009;23:1679─88; 8. Martínez E, et al. CROI 2013. Oral presentation 772. URL: http://www.retroconference.org/2013b/Abstracts/47369.htm. 9. Gallant JE, et al. JID 2013 [Epub ahead of print]. 10. DeJesus E, et al. Lancet 2012;379:2429–38. 11. Sax PE, et al. Lancet 2012;379:2439–48. 12. Soriano V, et al. Antivir Ther 2011;16:339–48. 13. Daar ES, et al. Ann Intern Med 2011;154:445–56. 14. van Leth F, et al. Lancet 2004;363:1253–63. 15. Molina J-M, et al. Lancet 2011;378:238–46. 16. Cohen CJ, et al. Lancet 2011;378:229–37. 17. European Medicines Agency http://www.ema.europa.eu (Accessed Apr 2013). 18. ATRIPLA SmPC Available at: http://www.ema.europa.eu Last updated 12/02/2013 (Accessed Apr 2013). 19. Raffi et al. Lancet. 2013;381:735-43. 20. Walmsley S, et al. ICAAC 2012, San Francisco, USA. Oral abstract H-556b http://www.natap.org/2012/ICAAC/ICAAC_06.htm. 21. Cohen C et al. HIV11 2012. Oral presentation O425. URL: http://natap.org/2012/interHIV/InterHIV_15.htm. 22. Feinberg J et al. ICAAC 2013. Abstract H-1464a. http://www.icaaconline.com/php/icaac2013abstracts/start.htm. Toxicities: delayed recognition Strong Delay Drug / class FDA approval Toxicity signal (years) Zidovudine1 1987 Lipoatrophy 1999 12 Stavudine 1 1994 Lipoatrophy 1999 5 Hepatitis / rash at Nevirapine 1996 2005 9 higher CD4 PIs2 1996- Heart attack 2003 7 Efavirenz3 1998 Suicidality 2013 15 Tenofovir4 2001 Kidney disease 2006 5 Tenofovir5 2001 Fracture 2013 12 Raltegravir6 2007 Myopathy 2012 5 1. Saint-Marc T et al, AIDS 1999;13:1659–1667. Cross-sectional, multicentre study. N=43. 2. Friis-Mollen N et al, N Engl J Med 2003;349:1993–2003. Prospective observational study. N=23,468. 3. Mollan et al, IDSA 2013;abstract 670. Cross-study analysis. N=5332 ARV-naive patients (4 studies). 4. Cooper RD et al, Clin Infect Dis 2010; 51:496–505. Meta-analysis of 17 trials (9 RCTs) 5. Bedimo R et al, AIDS 2012;26:825–831. Retrospective analysis. N=56,600. 6. Lee FJ et al, J Acquir Immune Defic Syndr 2013;62:525–533. Cross-sectional, 2-arm prevalence study. N=318. Efficacy: newer treatments outperform EFV Favours EFV Favours Comparator -12% +12% GS-1021 (STB vs. ATR) N=700 -1.6 3.6 8.8 Week 48: Non-inferiority shown 88% vs. 84% (Snapshot) 0.7 5.1 9.4 GS-102/103/1042 (STB vs. ATR) N=1124 Week 48 (Pooled): Statistically significant 89% vs. 84% (Snapshot) higher VL response 3 -1.1 4.1 9.2 STaR (CPA vs. ATR) N=786 Week 48: Non-inferiority shown 86% vs. 82% (Snapshot) 1.1 13.4 89% vs. 82% (Snapshot) 7.2 Week 48: Statistically significant higher VL BLVL ≤100,000 cpm response -1.9 4.2 10.3 STARTMRK4 (RAL vs. EFV) N=566 Week 48: Non-inferiority shown 86% vs. 82% (ITT, NC=F) 1.7 9.5 17.3 Week 240: Statistically significant 71% vs. 61% (ITT, NC=F) higher VL response SINGLE5 (DTG vs. ATR) N=833 2.5 7.4 12.3 Week 48: Statistically significant superior VL 88% vs. 81% (Snapshot) response ECHO/THRIVE6 (RPV vs. ATR) N=1368 -1.7 2.4 6.6 Week 48: Non-inferiority shown 83% vs. 80% (Snapshot) 1.6 6.6 11.5 90% vs. 84% (TLOVR) Week 48: Statistically significant higher VL response BLVL ≤100,000 cpm -20 -15 -10 -5 0 5 10 15 20 Differences in Percentages (95% CI) Newer ARVs have demonstrated higher rates of virologic suppression compared to EFV-based regimens in HIV-1 infected ART-naïve patients 1. Sax P, et al. Lancet 2012;379:2429–38 4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File 6. Cohen C, et al. JAIDS 2012;60:33-42 ACTG 5257 - atazanavir, raltegravir and darunavir virologically equivalent in naive patients but significant differences for tolerability Phase III DTG trials in treatment-naïve ADULT subjects with HIV Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of: SINGLE1 N=833 • DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC FDC placebo • EFV/TDF/FTC FDC (QD) plus DTG and ABC/3TC FDC placebo Phase IIIb non-inferiority, randomised, active-controlled, multicentre, FLAMINGO2 N=484 open-label study of: • DTG (50 mg QD) + 2 NRTIs • DRV/r (800 mg*/100 mg QD) + 2 NRTIs Phase III non-inferiority, randomised, double-blind, SPRING-23,4 N=822 double-dummy, multicentre study of: • DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs • RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs *Given as 2 x 400 mg tablets NRTI, nucleoside reverse transcriptase inhibitor 1. Walmsley S et al. N Engl J Med 2013;369:1807-1818 2. Clotet B, et al. Lancet 2014 March 31 [Epub ahead of print] DRV/r, darunavir/ritonavir; QD, once daily; BID, twice daily; 3. Raffi F et al. Lancet 2013;381:735–43 FDC, fixed-dose combination 4. Raffi F et al. Lancet 2013. doi.org/10.1016/S1473-3099(13)70257-3 SINGLE: Week 96 virologic suppression (<50 copies/mL snapshot) At Week 96: DTG + ABC/3TC was superior to EFV/FTC/TDF. Statistically higher response driven by withdrawals for AEs: 3% (DTG arm) vs. 11% (EFV arm) Protocol-defined VFs (confirmed ≥ 50 copies/mL at or after W24) were identical in both arms at Weeks 48 (4%) and 96 (6%) DTG + ABC/3TC QD EFV/TDF/FTC QD 100 DTG: 80% 80 EFV: 72% 60 Week 96 adjusted difference in response (95% CI): 40 +8.0% (+2.3% to +13.8%); P=0.006 20 Proportion of % patients, 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Week Adjusted mean CD4 changes from baseline: 325 cells/mm3 (DTG arm) and 281 cells/mm3 (EFV arm) 3TC, lamivudine; ABC, abacavir; CI, confidence interval; DTG. Dolutegravir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disporoxil fumarate; VF, virologic failure Walmsley S, et al. CROI 2014; Boston, MA. Abs. 14543. Dolutegravir vs efavirenz • At W96, DTG + ABC/3TC was superior to EFV/FTC/TDF [statistically higher responses; 8% (+2.3%, 13.8%)] which was driven by withdrawals due to AEs in the EFV/FTC/TDF arm (3% vs. 11%) DTG: Treatment-emergent resistance through 48 weeks DTG has demonstrated a favourable resistance profile in several studies to date SINGLE study (48 weeks), n1 DTG + ABC/3TC OD (N=414) EFV/TDF/FTC OD (N=419) INI resistant mutations 0 0 NRTI resistant mutations 0 1 (K65K/R) NNRTI resistant mutations 0 4 (K101E, K103N, G190G/A)* SPRING-2 study (48 weeks), n2 DTG OD (N=411) RAL BD (N=411) INI resistant mutations 0 1† NRTI resistant mutations 0 4†‡ FLAMINGO study (48 weeks), n3 DTG OD (N=242) DRV/r OD (N=245) Treatment-emergent primary mutations (INI, NRTI, PI) 0 0 *K101E (n=1); K103N (n=1); G190G/A (n=1); K103N + G190G/A (n=1).
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