Impact of integrase inhibitors on the HIV epidemic in Asia Matthew Law APACC, Hong Kong, 27 June 2018
What might be the impact of integrase inhibitors on the HIV epidemic in Asia Matthew Law APACC, Hong Kong, 27 June 2018
ART coverage end 2016 Lorem ipsum WHO WHO 2017 Source: Global Health Observatory (http://www.who.in/gho) 3
ART use in Asia TAHOD-LITE 10 sites Cambodia, Hong Kong, India, Indonesia, Singapore, South Korea, Taiwan, Vietnam Generalisability 4
IeDEA TREAT Asia network 5
Region 1: North America Canada United States Region 2: Caribbean, Central and South America Argentina Brazil Chile Haiti Honduras Mexico Peru Region 5: Asia and Australia Australia / NZ Cambodia China Hong Kong India Indonesia Japan Malaysia Philippines Singapore South Korea Taiwan Thailand Vietnam Region 8: West Africa Benin Burkina Faso Côte d Ivoire Gambia Ghana Guinea-Bissau Mali Nigeria Senegal Togo Region 9: Central Africa Burundi Cameroon Rwanda Region 11: Southern Africa Botswana Lesotho Malawi Mozambique South Africa Zambia Zimbabwe Region 10: East Africa Kenya Tanzania Uganda
ART use in TAHOD-LITE 33,233 started ART Median 2010 (IQR 2006 to 2012) 69% male Median age 36 years (IQR 30 to 42) Median CD4 154 cells/µl (IQR 49 to 268) 30%NK Median log viral load 5.0 (IQR 4.4 to 5.5) 80%NK 12% anti-hcv (58% not tested) 8% HBsAg (43% not tested) 7
Proportion of patients starting ART in period (%) Impact of INSTIs in Asia ART use in TAHOD-LITE First regimen over time NRTI backbone NNRTI 100 100 80 80 60 60 40 40 20 20 0 2006-09 2010-13 2014-16 0 2006-09 2010-13 2014-16 NRTI combination d4t+3tc/ftc AZT+3TC/FTC TDF+3TC/FTC ABC+3TC/FTC Other NNRTI EFV NVP Other NNRTI Non-NNRTI 8
Proportion of patients starting second ART in period (%) Impact of INSTIs in Asia ART use in TAHOD-LITE Second regimen NRTI backbone Third drug 100 100 80 80 60 60 40 40 20 20 0 2006-09 2010-13 2014-16 0 2006-09 2010-13 2014-16 NRTI combination d4t+3tc/ftc AZT+3TC/FTC TDF+3TC/FTC ABC+3TC/FTC Other PI LPV ATV Other PI Non-PI 9
Probability of being on second regimen Impact of INSTIs in Asia ART use in Asia First and second regimen durability First regimen 1.0 1.0 Second regimen 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 Years 0.0 0 1 2 3 4 Years 2006-09 2010-13 2014-16 9552 7067 5861 5054 4364 11251 8163 6727 5633 3971 5375 2506 1038 133 0 2006-09 2010-13 2014-16 1435 1038 872 754 652 3535 2682 2242 1909 1237 3010 1609 965 98 0 2006-09 2010-13 2014-16 2006-09 2010-13 2014-16 10
Proportion (%) Impact of INSTIs in Asia ART use in TAHOD-LITE First, second and third ART regimen 18000 100 16000 14000 12000 10000 8000 6000 4000 2000 0 80 60 40 20 0 2006 2007 2008 2009 2010 2011 2012 Calendar Year 2013 2014 2015 2016 2006 2007 2008 2009 2010 2011 2012 Calendar Year 2013 2014 2015 2016 ART regimen First Second Third ART regimen First Second Third 11
Proportion (%) Impact of INSTIs in Asia ART use in TAHOD-LITE Current drug class 18000 100 16000 14000 80 12000 10000 60 8000 6000 40 4000 20 2000 0 0 2006 2007 2008 2009 2010 2011 2012 Calendar Year 2013 2014 2015 2016 2006 2007 2008 2009 2010 2011 2012 Calendar Year 2013 2014 2015 2016 ART class Insti PI NNRTI NRTI Other ART regimen Insti PI NNRTI NRTI Other 12
ART use in TAHOD-LITE ART coverage overall 40-60% Growing need for good second and third line options Limited INSTI use to present Limited impact on treatment guidelines 14
INSTI effectiveness 15
INSTI effectiveness INSTI as first-line ART At least equivalent virological suppression Fewer adverse events Better durability DTG and RAL no CYP3A4-associated drug interactions 16 Walmsley et al. NEJM 2013;369:1807-18 Stellbrink et al. AIDS 2013;27:1771-8 Clotet et al. Lancet 2014;383:2222-31 Lennox et al. Ann Intern Med 2014;161:461-71 Molina et al. Lancet HIV 2015:2;e127-36 Kanters et al. Lancet HIV 2016:3;e510-20
INSTI effectiveness INSTI as first-line ART At least equivalent virological suppression Fewer adverse events Better durability DTG and RAL no CYP3A4-associated drug interactions Switch to INSTI non-inferior to continuing suppressive ART Simplify to 2-drug regimen 17 Trottier et al. Antivir Ther 2017:22;295-305
INSTI effectiveness INSTI as first-line ART At least equivalent virological suppression Fewer adverse events Better durability DTG and RAL no CYP3A4-associated drug interactions Switch to INSTI non-inferior to continuing suppressive ART INSTI+PI non-inferior to 2N+PI as second line 18 Boyd et al. Lancet 2013:381;2091-99 Paton et al. NEJM 2014:371;234-47 LaRosa et al. Lancet HIV 2016:3;e247-58
INSTI effectiveness INSTI as first-line ART At least equivalent virological suppression Fewer adverse events Better durability DTG and RAL no CYP3A4-associated drug interactions Switch to INSTI non-inferior to continuing suppressive ART INSTI+PI non-inferior to 2N+PI as second line 2N+INSTI superior to 2N+PI as second line 19 Aboud et al. DAWNING study. 9 th IAS Conference on HIV Science; 2017; Paris, France.
TLD generic fixed dose combination ~US$75 per patient per year in LMICs Cheaper Could we treat more patients for same money? 20
Unitaid modelling Lorem ipsum 21
ART coverage by sex among adults, 2016 Source: UNAIDS/WHO estimates.
TLD fixed dose combination ~US$75 per patient per year in LMICs Generic, fixed dose combination, one pill/day, first and second line ART TLD 2N+EFV Effective PI based third line ART possible 23
DAWNING 2N+DTG vs 2N+LPVr Week 24 virological suppression 257/312 (82%) vs 215/312 (69%) DSMB halted the trial 24
DAWNING 2N+DTG vs 2N+LPVr Week 24 virological suppression 257/312 (82%) vs 215/312 (69%) DSMB halted the trial Resistance testing at baseline Had to use at least one fully active NRTI 25
TLD FDC as second line Resistance testing not available in most LMICs Raises the question of the effectiveness of TLD FDC as second line in a public health approach 26
D 2 EFT Intervention Initial design 1:1 allocation of SOC (DRV/r+2NRTI) versus DRV/r+DTG Resistance testing in ~30% of participants Nucleosides rotated per WHO algorithm if no resistance testing 610 total participants, 12% non-inferiority margin, 90% power Primary endpoint 48w with DSMB review of 24w data at 50% accrual
D 2 EFT adaptation Multi-arm multi-stage design MAMS design Variable allocation of SOC (DRV/r+2NRTI) versus DRV/r+DTG versus TLD 1,010 total participants, 12% non-inferiority margin, 90% power for arm 1 vs 2, 88% 1 vs 3, 2 vs 3 88% as secondary comparison (i.e. does allow intervention arms to be compared) Primary endpoint 48w with DSMB review of 12w and 24w data at 100 subjects
D 2 EFT adaptation David Cooper Mark Polizzotto, Simone Jacoby Absar Noorul 29
D 2 EFT global partnership TAHOD-L 30
Funding Partnership
D 2 EFT timelines Opening of first sites to third arm July 2018 Final sites (new) to third arm quarter 4 2018 or first quarter 2019 Safety readout by July 2019 Accrual complete December 2019 Primary endpoint December 2020 32
DTG and pregnancy Botswana cohort 4 cases of neural tube defects in 426 women receiving DTG at conception Further work underway If confirmed 30-50% of HIV-positive people in our region are women 33
Treatment as prevention Could move to widespread use of INSTIs help reduce HIV transmission? 34
UNAIDS/WHO estimates HIV testing and care continuum by WHO region (2016)
Treatment as prevention Could move to widespread use of INSTIs help reduce HIV transmission? Potentially a bit Increase treatment uptake and durability Increase proportion <1,000 copies/ml 36
Conclusion Growing need for effective, simple, cheap second and third line options INSTIs could help meet that need Questions around safety and efficacy remain Really do need further trial and cohort data 37
TAHOD-LITE study members PS Ly and V Khol, National Center for HIV/AIDS, Dermatology & STDs, Phnom Penh, Cambodia; MP Lee, PCK Li, W Lam and YT Chan, Queen Elizabeth Hospital, Hong Kong SAR; N Kumarasamy, S Saghayam and C Ezhilarasi, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), YRGCARE Medical Centre, VHS, Chennai, India; S Pujari, K Joshi, S Gaikwad and A Chitalikar, Institute of Infectious Diseases, Pune, India; TP Merati, DN Wirawan and F Yuliana, Faculty of Medicine Udayana University & Sanglah Hospital, Bali, Indonesia; OT Ng, PL Lim, LS Lee and Z Ferdous, Tan Tock Seng Hospital, Singapore; JY Choi, Na S and JM Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; WW Wong, WW Ku and PC Wu, Taipei Veterans General Hospital, Taipei, Taiwan; CD Do, AV Ngo and LT Nguyen, Bach Mai Hospital, Hanoi, Vietnam; KV Nguyen, HV Bui, DTH Nguyen and DT Nguyen, National Hospital for Tropical Diseases, Hanoi, Vietnam; AH Sohn, JL Ross and B Petersen, TREAT Asia, amfar - The Foundation for AIDS Research, Bangkok, Thailand; R Bijker, A Jiamsakul, D Rupasinghe and MG Law, Kirby Institute, UNSW Sydney, Australia 38