post-croi 2018 nieuwe ontwikkelingen-art Kees Brinkman

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1 post-croi 2018 nieuwe ontwikkelingen-art Kees Brinkman

2 Disclosure Voor bijeenkomst mogelijk relevante relaties met bedrijven adviesraad Gilead Janssen MSD Viiv Bedrijfsnamen spreker virology education

3 inhoud HIV care in USA: persons at risk cascade of care: USA vs NL diagnosed: regional differences retained in care: how to improve how to treat: cart next 25 years cascade including prevention: PrEP

6 1:578 associatie met : armoede opleidingsniveau verzekering 1:51

9 hiv cascade PLWHIV cascade of treatment: - healthcare system - which cart Dx cart <100

10 USA: 85% diagnosed, loss in retention (20%)

11 100% 93% 75% 57% 68% best practice SF: 93% diagnosed, but also loss of retention

12 88% 88% 93% ook in NL: vooral groot verschil in % diagnosed

13 retention in care:

14 how to improve retention in care:

15 how to improve/maintain efficacy of cart

16 Treatment and management strategies Reducing ART exposure New agents Different ART formulations Drug dose Dosing frequency Number of drugs Investigational ARTs Monoclonal antibodies Long-acting oral Implantable Long-acting injectable

HIV drug pipeline under clinical evaluation (Phase I III) Entry inhibitors Monoclonal antibodies (mab) NRTIs/NtRTIs ( nukes ) NNRTIs ( non-nukes ) Integrase inhibitors Fostemsavir (GSK-934; FTR)

17 HIV drug pipeline under clinical evaluation (Phase I III) Entry inhibitors Monoclonal antibodies (mab) NRTIs/NtRTIs ( nukes ) NNRTIs ( non-nukes ) Integrase inhibitors Fostemsavir (GSK-934; FTR) UB-421 (CD4 receptor) Cenicriviroc (TBR-652; CVC) PRO-140 (CCR5 receptor) Doravirine (MK-1439) Bictegravir (GS-9883) Elsulfavirine (VM1500) Cabotegravir-LAI (GSK-744; CAB) Sifuvirtide (FS-0101) Ibalizumab (TMB-355) Rilpivirine-LAI (TMC278; RPV) Albuvirtide (FB006M; ABT) VRC01 Dapivirine (TMC120; DPV) EFdA (MK-8591) GS-9131 Protease inhibitors Capsid inhibitors GS-PI1 GS-CA1 Maturation inhibitors Unique/ unknown MoA GSK MK-8507 ABX464 LEDGINs VRC01-LS 8 PC-1005 (MIV150/zinc acetate) 2 Fusion 3 1 MK-2048 Attachment Maturation Reverse transcription 5 Viral DNA Chemokine co-receptor 4 CD4 H I V L 6 Transcription Integration I F E C Y C L E Translation 7 Assembly/cleavage

18 Modes of delivery ABX464 Bictegravir (GS-9883) Cenicriviroc (TBR-652; CVC) Doravirine (MK-1439) Doravirine EFdA (MK-8591) Elsulfavirine (VM1500) Fostemsavir (GSK-934; FTR) GS-9131 GS-PI1 GS-CA1 GSK MK-8507 ORAL INJECTABLE Albuvirtide (FB006M; ABT) Ibalizumab (TMB-355) PRO-140 (CCR5 receptor) Sifuvirtide (FS-0101) UB-421 (CD4 receptor) VRC01 VRC01-LS OTHER (TOPICAL, IMPLANTABLE, GEL) LONG-ACTING INJECTABLE Dapivirine (TMC120; DPV) MK-2048 PC-1005 (MIV- 150/zinc acetate) Cabotegravir-LAI (GSK-744; CAB) Rilpivirine-LAI (TMC278; RPV) LEDGINs Not currently under clinical investigation

Will there be demand for LA injectable or implantable ART?

from women using contraception: multiple modalities different modalities at different

19 Will there be demand for LA injectable or implantable ART? Patients in LATTE-2 trial preferred LA injectable CAB/RPV to taking pills 1,2 Lessons from women using contraception: multiple modalities different modalities at different times variety of options makes it easier to adhere Oral Could any be administered at home by patients? Topical/ Implantable Injectable CAB, cabotegravir; LA, long-acting; RPV, rilpivirine. 1. Margolis DA, et al. Lancet 2017;390: ; 2. Eron J, et al. IAS 2017, Paris, France; abstract #MOAX0205LB.

28 Chloë Orkin continued:

First-line ART Guidelines: Recommended and preferred regimens GUIDELINES NRTI BACKBONE NNRTI INSTI PI EACS (2017) 1 TAF/FTC TDF/FTC ABC/3TC* RPV* DTG RAL EVG DRV/c or /r DHHS (2017) 2 TAF/FTC TDF/FTC

EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS USA, International Antiviral Society USA; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase

29 First-line ART Guidelines: Recommended and preferred regimens GUIDELINES NRTI BACKBONE NNRTI INSTI PI EACS (2017) 1 TAF/FTC TDF/FTC ABC/3TC* RPV* DTG RAL EVG DRV/c or /r DHHS (2017) 2 TAF/FTC TDF/FTC ABC/3TC* DTG RAL EVG/c IAS USA (2016) 3 TAF/FTC ABC/3TC* DTG RAL EVG/c BHIVA (2016) 4 TAF/FTC TDF/FTC RPV* DTG RAL EVG/c DRV/r ATV/r WHO (2016) 5 TDF/XTC EFV *Use recommended only if baseline viral load <100,000 copies/ml. 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; BHIVA, British HIV Association; c, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS USA, International Antiviral Society USA; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization; XTC, FTC or 3TC. 1. EACS Guidelines Version 9.0. Available from: Accessed January 2018; 2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: Accessed January 2018; 3. Günthard HF, et al. JAMA 2016;316: ; 4. BHIVA Guidelines. Available from: Accessed January 2018; 5. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Available from: Accessed January 2018.

30 First-line ART Recommended, preferred regimens + ALTERNATIVE GUIDELINES NRTI BACKBONE NNRTI INSTI PI NRTI-REDUCING EACS (2017) 1 TAF/FTC TDF/FTC ABC/3TC* RPV* EFV DTG RAL EVG DRV/c or /r ATV/c or /r DRV/c or /r + RAL LPV/r + XTC DHHS (2017) 2 TAF/FTC TDF/FTC ABC/3TC* EFV RPV* DTG RAL EVG/c ATV/c or /r DRV/c or /r DRV/c or /r + RAL IAS USA (2016) 3 TAF/FTC ABC/3TC* EFV RPV DTG RAL EVG/c DRV /c or /r DRV/c or /r + RAL DRV/c or /r + DTG DRV/c or /r + XTC BHIVA (2016) 4 TAF/FTC TDF/FTC ABC/3TC* RPV* EFV DTG RAL EVG/c DRV/r ATV/r DRV/c or /r + RAL WHO (2016) 5 TDF/XTC AZT/XTC EFV EFV 400 NVP DTG *Use recommended only if baseline viral load <100,000 copies/ml. 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; BHIVA, British HIV Association; c, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS USA, International Antiviral Society USA; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization; XTC, FTC or 3TC. 1. EACS Guidelines Version 9.0. Available from: Accessed January 2018; 2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: Accessed January 2018; 3. Günthard HF, et al. JAMA 2016;316: ; 4. BHIVA Guidelines. Available from: Accessed January 2018; 5. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Available from: Accessed January 2018.

31 Proportion of patients (%) First-line ART Determinants of efficacy by FDA snapshot VL <50 c/ml driven by: Baseline VL Barrier to resistance No data in window: Disengagement from care Tolerability (discontinuations) Safety (withdrawals) 0 Virologic response (VL <50 c/ml) VL 50 c/ml No data in window FDA, The Food and Drug Administration; VL, viral load.

32 Proportion of patients (%) First-line ART Determinants of efficacy by FDA snapshot VL <50 c/ml driven by: Baseline viral load Barrier to resistance No data in window: Disengagement from care Tolerability (discontinuations) Safety (withdrawals) 0 Virologic response (VL <50 c/ml) VL 50 c/ml No data in window FDA, The Food and Drug Administration; VL, viral load.

Virologically suppressed patients (%) First-line ART Overall efficacy outcomes at Week 48 Efficacy outcomes difficult for new drugs to prove superiority.

ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al.

33 Virologically suppressed patients (%) First-line ART Overall efficacy outcomes at Week 48 Efficacy outcomes difficult for new drugs to prove superiority... ATV, atazanavir; BD, twice daily; BIC, bictegravir; c, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; QD, once daily; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al. AIDS 2008;22: ; 3. Lennox JL, et al. Lancet 2009;374: ; 4. Cohen CJ, et al. Lancet 2011;378:229 37; 5. Molina JM, et al. Lancet 2011;378:238 46; 6. Raffi F, et al. Lancet 2013;381:735 43; 7. Walmsley SL, et al. N Engl J Med 2013;369: ; 8. Clotet B, et al. Lancet 2014;383: ; 9. Sax PE, et al. Lancet 2015;385: ; 10. Squires K, et al. Lancet HIV 2016;3:e410 20; 11. Orrell C, et al. Lancet HIV 2017;4:e536 46; 12. Cahn P, et al. Lancet HIV 2017;4:e486 94; 13. TBA; 14. Sax PE, et al. Lancet 2017;390: ; 15. Gallant J, et al. Lancet 2017;390:

34 First-line ART Toward zero resistance: 2nd-generation INSTI studies STUDY FLAMINGO 1 ARIA 2 SINGLE 3 GS-1489 (ABC) 4 GS-1490 (TDF) 5 Drug DTG DTG DTG BIC DTG BIC DTG NRTI INSTI BIC, bictegravir. 2. Clotet B, et al. Lancet 2014;383: ; 2. Orrell C et al. Lancet HIV 2017;4:e536 46; 3. Walmsley SL, et al. N Engl J Med 2013;369: ; 4. Gallant J, et al. Lancet 2017;390: ; 5. Sax PE, et al. Lancet 2017;390:

Enhancing engagement = make meds convenient TRIPLE 2DR DRUG ATRIPLA 1 EVIPLERA 2 STRIBILD 3 TRIUMEQ 4 GENVOYA 5 ODEFSEY 6 SYMTUZA 7 BIKTARVY 8 JULUCA 9 COMPONENTS Generic FDC TDF/XTC/EFV TDF/FTC/RPV

interactions VL <100,000 Drug drug interactions Long-term data Gastric ph Licensed once-daily fixed-dose combinations. Pill sizes are not to scale. Filed for licensing: TDF/3TC/DOR (1439A) 1.

Updated June 2017. Accessed October 2017; 3. Stribild SmPC. Available from: https://www.medicines.org.uk/emc/medicine/27810. Updated June 2017. Accessed October 2017; 4. Triumeq SmPC.

35 Enhancing engagement = make meds convenient TRIPLE 2DR DRUG ATRIPLA 1 EVIPLERA 2 STRIBILD 3 TRIUMEQ 4 GENVOYA 5 ODEFSEY 6 SYMTUZA 7 BIKTARVY 8 JULUCA 9 COMPONENTS Generic FDC TDF/XTC/EFV TDF/FTC/RPV TDF/FTC/EVG/c ABC/3TC/DTG TAF/FTC/EVG/c TAF/FTC/RPV TAF/FTC/DRV/c TAF/BIC/FTC DTG/RPV CONSIDERATIONS Premorbid Psychiatric VL <100,000 Drug drug interactions HLAB*5701 co-infection Drug drug interactions VL <100,000 Drug drug interactions Long-term data Gastric ph Licensed once-daily fixed-dose combinations. Pill sizes are not to scale. Filed for licensing: TDF/3TC/DOR (1439A) 1. Atripla SmPC. Available from: Updated May Accessed October 2017; 2. Eviplera SmPC. Available from: Updated June Accessed October 2017; 3. Stribild SmPC. Available from: Updated June Accessed October 2017; 4. Triumeq SmPC. Available from: Updated January Accessed October 2017; 5. Genvoya SmPC. Available from: Updated September Accessed October 2017; 6. Odefsey SmPC. Available from: Updated September Accessed October 2017; 7. Symtuza SmPC. Available from: Updated September Accessed October 2017; 8. Biktarvy PI. Available from: Accessed February 2018; 9. Juluca SmPC. Available from: Updated November Accessed December 2017.

36 Virologically suppressed patients (%) First-line ART Overall efficacy outcomes at Week 48 Efficacy outcomes Women-only studies ATV, atazanavir; BD, twice daily; BIC, bictegravir; c, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; QD, once daily; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al. AIDS 2008;22: ; 3. Lennox JL, et al. Lancet 2009;374: ; 4. Cohen CJ, et al. Lancet 2011;378:229 37; 5. Molina JM, et al. Lancet 2011;378:238 46; 6. Raffi F, et al. Lancet 2013;381:735 43; 7. Walmsley SL, et al. N Engl J Med 2013;369: ; 8. Clotet B, et al. Lancet 2014;383: ; 9. Sax PE, et al. Lancet 2015;385: ; 10. Squires K, et al. Lancet HIV 2016;3:e410 20; 11. Orrell C, et al. Lancet HIV 2017;4:e536 46; 12. Cahn P, et al. Lancet HIV 2017;4:e486 94; 13. TBA; 14. Sax PE, et al. Lancet 2017;390: ; 15. Gallant J, et al. Lancet 2017;390:

Virologically suppressed patients (%) First-line ART Lower efficacy in VL >100,000 c/ml subgroup Efficacy outcomes Women-only studies ATV, atazanavir; BD, twice daily; BIC, bictegravir; c,

alafenamide fumarate; TDF, tenofovir disoproxil fumarate. 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al. AIDS 2008;22:1389 97; 3. Lennox JL, et al. Lancet 2009;374:796 806; 4.

37 Virologically suppressed patients (%) First-line ART Lower efficacy in VL >100,000 c/ml subgroup Efficacy outcomes Women-only studies ATV, atazanavir; BD, twice daily; BIC, bictegravir; c, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; QD, once daily; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al. AIDS 2008;22: ; 3. Lennox JL, et al. Lancet 2009;374: ; 4. Cohen CJ, et al. Lancet 2011;378:229 37; 5. Molina JM, et al. Lancet 2011;378:238 46; 6. Raffi F, et al. Lancet 2013;381:735 43; 7. Walmsley SL, et al. N Engl J Med 2013;369: ; 8. Clotet B, et al. Lancet 2014;383: ; 9. Sax PE, et al. Lancet 2015;385: ; 10. Squires K, et al. Lancet HIV 2016;3:e410 20; 11. Orrell C, et al. Lancet HIV 2017;4:e536 46; 12. Cahn P, et al. Lancet HIV 2017;4:e486 94; 13. TBA; 14. Sax PE, et al. Lancet 2017;390: ; 15. Gallant J, et al. Lancet 2017;390:

First-line ART Who is represented in these studies? Trials where participants are: 50% white >70% male 100% CD4 >300 >75% VL <100,000 1. Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al.

38 First-line ART Who is represented in these studies? Trials where participants are: 50% white >70% male 100% CD4 >300 >75% VL <100, Molina JM, et al. Lancet 2008;372:646 55; 2. Ortiz R, et al. AIDS 2008;22: ; 3. Lennox JL, et al. Lancet 2009;374: ; 4. Cohen CJ, et al. Lancet 2011;378:229 37; 5. Molina JM, et al. Lancet 2011;378:238 46; 6. Raffi F, et al. Lancet 2013;381:735 43; 7. Walmsley SL, et al. N Engl J Med 2013;369: ; 8. Clotet B, et al. Lancet 2014;383: ; 9. Sax PE, et al. Lancet 2015;385: ; 10. Squires K, et al. Lancet HIV 2016;3:e410 20; 11. Orrell C, et al. Lancet HIV 2017;4:e536 46; 12. Cahn P, et al. Lancet HIV 2017;4:e486 94; 13. TBA; 14. Sax PE, et al. Lancet 2017;390: ; 15. Gallant J, et al. Lancet 2017;390:

39 First-line ART We need longer term data beyond 96 and 192 weeks Trials enrolling: Older adults Women Trans and non-binary Ethnic diversity Adolescents Injecting drug users HCV and HBV co-infected CDC C Comorbidities allowed

40 When to start Immediate ART? START study = Start regardless of CD4 count 48 h U&E LFT FBC VL HLA B5701 Resistance INSIGHT START Study Group, et al. N Engl J Med 2015;373: : CD4 Rosen et al Plos medicine 2016 Koenig et al PLOS medicine 2017 Bacon et al.cro! year vs? Engagement with care? Infrastructure? Resistance? Virologic outcomes? Safety

41 First-line ART how to choose... bictegravir or dolutegravir? naieve study: non inferior

48 First-line ART TAF vs TDF or ABC GS-104/111 1,2 GS EVG/c + TAF/FTC vs TDF/FTC TAF: favorable renal biomarkers and BMD No renal or bone discontinuations to Week 144 TAF/FTC/BIC vs ABC/3TC/DTG No differences in renal or bone biomarkers at Week 48 3TC, lamivudine; ABC, abacavir; BIC, bictegravir; BMD, bone mineral density; c, cobicistat; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF tenofovir disoproxil fumarate. 1. Sax PE, et al. Lancet 2015;385: ; 2. Arribas JR, et al. CROI 2017, Seattle, WA, United States; poster #453; 3. Gallant J, et al. Lancet 2017;390: Chloë Orkin

49 First-line ART triple or duo...?

50 DHHS Guidelines: Summary of Initial ART Recommendations - October 2017 Recommended Initial Regimens for Most People With HIV DTG/ABC/3TC DTG + FTC/(TAF or TDF) EVG/COBI/FTC/(TAF or TDF) RAL + FTC/(TAF or TDF) Recommendations may differ based on baseline HIV-1 RNA, CD4+ cell count, CrCl, egfr, HLA-B*5701 status, HBsAg status, and osteoporosis status Separate list of Recommended Initial Regimens in Certain Clinical Situations includes PIs, NNRTIs, and other INSTI combination regimens Dual therapy may be considered when ABC, TAF, and TDF cannot be used: DRV/RTV + RAL (if HIV RNA < 100,000 copies/ml and CD4+ > 200 cells/mm 3 ), LPV/RTV + 3TC Not currently recommended: DTG + 3TC, DRV/RTV + 3TC DHHS guidelines. October Slide credit: clinicaloptions.com

51 ACTG A5353: DTG + 3TC for ART-Naive Pts Single-arm phase II study ART-naive pts with HIV-1 RNA 1000 and < 500,000 copies/ml; no RT, INSTI, major PI resistance mutations (N = 120) DTG 50 mg + 3TC 300 mg Primary Endpoint Wk 24 Virologic Outcome at Wk 24, n (%) Baseline HIV-1 RNA, copies/ml > 100,000 (n = 37) 100,000 (n = 83) Total (N = 120) Success* 33 (89) 75 (90) 108 (90) Nonsuccess 3 (8) 2 (2) 5 (4) No data 1 (3) 6 (7) 7 (6) n = 3 with PDVF; n = 1 with emergent M184V and R263R/K mixture All 3 pts had DTG levels reflective of suboptimal adherence *HIV-1 RNA < 50 copies/ml. Taiwo BO, et al. IAS Abstract MOAB0107LB. Slide credit: clinicaloptions.com

52 Selected Studies of Boosted PI Based Initial Dual Therapy Study N Regimen Results NEAT001 [1] 805 DRV/RTV + RAL Similar efficacy vs DRV/RTV + FTC/TDF Poor efficacy in pts with high HIV-1 RNA, low CD4+ cell counts GARDEL [2] 426 LPV/RTV + 3TC Similar efficacy vs LPV/RTV + 2 NRTIs SPARTAN [3] 94 ATV + RAL ANDES [4] 145 DRV/RTV + 3TC *Interim analysis. Similar virologic suppression, higher VF and hyperbilirubinemia rates vs ATV/RTV + FTC/TDF Similar efficacy vs DRV/RTV + 3TC/TDF* Efficacy maintained when BL HIV-1 RNA > 100,000 copies/ml 1. Raffi F, et al. Lancet. 2014;384: Cahn P, et al. EACS Abstract PS10/4. 3. Kozal MJ, et al. HIV Clin Trials. 2012;13: Sued O, et al. IAS Abstract MOAB0106LB. Slide credit: clinicaloptions.com

53 ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF in Treatment-Naive Pts at Wk 48 Open-label, randomized phase IV study Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 (FDA snapshot) Stratified by HIV-1 RNA ( or > 100,000 copies/ml) 24 Wks: Interim Analysis 48 Wks: Primary Endpoint ART-naive pts with HIV-1 RNA > 1000 copies/ml, no NRTI or PI resistance, and HBsAg negative (N = 145) DRV/RTV + 3TC* (n = 75) DRV/RTV + 3TC/TDF (n = 70) *DRV/RTV 800/100 mg QD + 3TC 300 mg QD. DRV/RTV 800/100 mg QD + 3TC/TDF 300/300 mg QD. Figueroa MI, et al. CROI Abstract 489. Slide credit: clinicaloptions.com

54 Pts (%) ANDES: Efficacy and Safety At Wk 48 HIV-1 RNA < 50 copies/ml at Wk 48 (ITT) DRV/RTV + 3TC DRV/RTV + 3TC/TDF Treatment difference (HIV-1 RNA < 50 c/ml; ITT snapshot): All pts: -1.0% (95% CI: -7.5% to 5.6%) All Pts n/n = 70/75 66/70 Pts With BL HIV-1 RNA > 100,000 c/ml (n = 35) Pts with high BL HIV-1 RNA: -1.4 (95% CI: to 14.4) No significant difference in AEs leading to d/c, serious AEs, or deaths between arms TC change from BL significantly greater with dual ART vs triple ART (19% vs 4%; P =.01); LDL-C and TG trended toward greater increases with dual ART Figueroa MI, et al. CROI Abstract 489. Reproduced with permission. Slide credit: clinicaloptions.com

Switching when VL <50 c/ml Principles of Switch: 2017 Guidelines Switch safely and for a good reason Review ART history, genotype, interactions, co-infection Consider efficacy-based triple-therapy

55 Switching when VL <50 c/ml Principles of Switch: 2017 Guidelines Switch safely and for a good reason Review ART history, genotype, interactions, co-infection Consider efficacy-based triple-therapy switch Consider efficacy-based 2DR switch DHHS Guidelines 3TC + PI/r-based 1 : DRV/r or /c + 3TC ATV/r or /c + 3TC INSTI + NNRTI 1 : DTG + RPV 3TC + PI/r-based 2 : DRV/r + 3TC ATV/r + 3TC LPV/r + 3TC INSTI + NNRTI 2 : DTG + RPV 2DR, two-drug regimen; 3TC, lamivudine; ART, antiretroviral therapy; ATV, atazanavir; c, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; r, ritonavir; RPV, rilpivirine; VL, viral load. 1. EACS Guidelines Version 9.0. Available from: Accessed January 2018; 2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: Accessed January Chloë Orkin

56 Switching when VL <50 c/ml Comparative Safety data studies efficacy of studies 2DR n=100 of 2DR n=100 2DR 2DR bpi + MVC bpi + INSTI bpi + 3TC NNRTI + INSTI MARCH 2 HARNESS 3 SALT, ATLAS 4,5 SWORD 1 & 2 8 bpi + MVC vs bpi + 2 NRTIs N= % ATV/r + RAL vs ATV/r + TDF/FTC N= % ATV/r + 3TC vs ATV/r + 2 NRTIs N=286; %, +9.8% OLE 6 DTG + RPV vs CAR (NRTI + other) N= % LATTE 9 LPV/r + 3TC vs LPV/r + 2NRTIs N= % CAB + RPV (oral) vs NRTI+ EFV N= % Difference = % of virologically suppressed patients in triple ART compared with 2DR at Week 48. Minus value is in favor of triple therapy; positive value is in favor of 2DR 1. Orkin C, et al. HIV Med 2018;19:18 32; 2. Pett SL, et al. Clin Infect Dis 2016;63:122 32; 3. van Lunzen J, et al. J Acquir Immune Defic Syndr 2016;71:538 43; 4. Perez-Molina JA, et al. Lancet Infect Dis 2015;15:775 84; 5. Di Giambenedetto S, et al. J Antimicrob Chemother 2017;72: ; 6. Arribas JR, et al. Lancet Infect Dis 2015;15:785 92; 7. Pulido F, et al. HIV Glasgow 2016, Glasgow, United Kingdom; abstract #0331; 8. Llibre JM, et al. CROI 2017, Seattle, WA, United States; abstract #44LB; 9. Margolis DA, et al. Lancet Infect Dis 2015;15: ; 10. Margolis DA, et al. AIDS 2016, Durban, South Africa; abstract #THAB0206LB. DUAL 7 DRV/r + 3TC vs DRV/r + 2NRTIs N=249-4% % difference >12% % difference <12% LATTE-2 10 CAB + RPV (IM) vs CAB+ ABC/3TC N=286 Q8W: +2.9% Q4W: +2.0% Chloë Orkin

Switching when VL <50 c/ml Comparative Safety data studies efficacy of studies 2DR n=100 of 2DR n=100 2DR 2DR bpi + MVC bpi + INSTI bpi + 3TC NNRTI + INSTI MARCH 2 HARNESS 3 SALT, ATLAS 4,5 SWORD 1 &

2% More studies awaited DTG/3TC DTG/DRV/r LA CAB + RPV TANGO DUALIS (NCT02486133) FLAIR (NCT02938520) ATLAS (NCT02951052) ATLAS-2M (NCT03299049) 1. Orkin Adapted C, et al.

57 Switching when VL <50 c/ml Comparative Safety data studies efficacy of studies 2DR n=100 of 2DR n=100 2DR 2DR bpi + MVC bpi + INSTI bpi + 3TC NNRTI + INSTI MARCH 2 HARNESS 3 SALT, ATLAS 4,5 SWORD 1 & 2 8 bpi + MVC vs bpi + 2 NRTIs N= % ATV/r + RAL vs ATV/r + TDF/FTC N= % ATV/r + 3TC vs ATV/r + 2 NRTIs N=286; %, +9.8% DTG + RPV vs CAR (NRTI + other) N= % More studies awaited DTG/3TC DTG/DRV/r LA CAB + RPV TANGO DUALIS (NCT ) FLAIR (NCT ) ATLAS (NCT ) ATLAS-2M (NCT ) 1. Orkin Adapted C, et al. HIV from Med clinicaloptions.com 2018;19:18 32; 2. Pett SL, et al. Clin Infect Dis 2016;63:122 32; 3. van Lunzen J, et al. J Acquir Immune Defic Syndr 2016;71:538 43; 4. Perez-Molina JA, et al. Lancet Infect Dis 2015;15:775 84; 5. Di Giambenedetto S, et al. J Antimicrob Chemother 2017;72: ; 6. Arribas JR, et al. Lancet Infect Dis 2015;15:785 92; 7. Pulido F, et al. HIV Glasgow 2016, Glasgow, United Kingdom; abstract #0331; 8. Llibre JM, et al. CROI 2017, Seattle, WA, United States; abstract #44LB; 9. Margolis DA, et al. Lancet Infect Dis 2015;15: ; 10. Margolis DA, et al. AIDS 2016, Durban, South Africa; abstract #THAB0206LB; Chloë Orkin

58 2DR questions for the future Data gaps Long-term data VL > 500,000 c/ml; Low CD4 Resistance Pregnancy Inflammation Sanctuary site penetration Viral reservoir Immune senescence Chloë Orkin

59 2DR questions for the future Data gaps Long-term data VL > 500,000 c/ml; Low CD4 Resistance Pregnancy Inflammation Sanctuary site penetration Viral reservoir Immune senescence Questions that occur in clinic How much adherence is enough? Is it ok to monitor VL for 2DR twice or once a year? Can it be used for those with unclear history of suppression/unknown genotype at failure? How does one salvage a failure on 2DR? Chloë Orkin

60 Impact of M184V on Virologic Efficacy of Switch to 3TC-Based Dual ART Retrospective observational study comparing efficacy of 3TC-based dual ART for pts with or without M184V history in Antiretroviral Resistance Cohort Analysis database (N = 436) Inclusion criteria: HIV RNA 50 copies/ml, switching to dual therapy (3TC + either PI/RTV or INSTI), 1 prior genotyping M184V determined in historic genotypic resistance tests and last genotyping Primary endpoint: time to virologic failure in M184V-positive vs M184V-negative pts Dual Therapy Initiated, % Pts (N = 436) DRV/RTV + 3TC 36 DTG + 3TC 29 ATV/RTV + 3TC 24 LPV/RTV + 3TC 10 RAL + 3TC 1 Gagliardini R, et al. CROI Abstract 498. Slide credit: clinicaloptions.com

61 Proportion Free From VF M184V and Switch to 3TC-Based Dual ART: Efficacy Estimated Probability of Remaining VF-Free on Dual Therapy* M184V+ overall M184V- overall M184V+ with time of viral suppression 6.6 yrs M184V- with time of viral suppression 6.6 yrs M184V+ with time of viral suppression 3 yrs M184V- with time of viral suppression 3 yrs Yrs From Dual ART Initiation Significantly higher 3-yr probability of remaining free from viral blip without vs with M184V (log-rank P =.016) M184V: 79.8% (95% CI: 67.8% to 91.8%) No M184V: 90.1% (95% CI: 84.0% to 96.2%) *VF: 2 HIV-1 RNA findings > 50 c/ml or 1 finding 200 c/ml. No VF in 21 pts on DTG + 3TC over median f/u of 10 mos. Viral blip: single HIV-1 RNA finding c/ml, not confirmed. Gagliardini R, et al. CROI Abstract 498. Reproduced with permission. Slide credit: clinicaloptions.com

62 at risk volledige hiv cascade cascade of prevention: - education - condoms, PrEP PLWHIV Dx cart <100

74 conclusies HIV cascades: NL>>> USA regionale verschillen... nieuwe middelen weinig nieuwe middelen snel: doravirine? MK-8591 NL bictegravir ~ dolutegravir nieuwe combinaties (...): 2DR DGV/RLP.../3TC? PrEP: snelle reductie in nieuwe infecties (Australie) ( nu ook in NL; wie doet wat/waar?

75 thanks to Cloë Orkin

84 Study : Switch From Suppressive DTG/ABC/3TC to BIC/FTC/TAF Randomized, double-blind, international, active-controlled phase III trial Primary endpoint: Wk 48 HIV-1 RNA 50 c/ml (FDA snapshot; noninferior. margin: 4%) Wk 48 Pts with HIV-1 RNA < 50 c/ml for 3 mos on DTG/ABC/3TC*; egfr CG 50 ml/min; no active HBV; no known resistance to study drugs (N = 563) BIC/FTC/TAF (n = 282) DTG/ABC/3TC (n = 281) Open-label extension with BIC/FTC/TAF Baseline: male sex, 88% to 90%; black race, 21% to 22%; median age, yrs; median CD4+ cell count, cells/mm 3 ; median egfr CG, 101 ml/min *Could be STR or as separate components. All pts also received placebo tablets for comparator regimen. BIC/FTC/TAF 50/200/25 mg PO QD. DTG/ABC/3TC 50/600/300 mg PO QD. Molina J-M, et al. CROI Abstract O22. Slide credit: clinicaloptions.com

85 Switch From Suppressive DTG/ABC/3TC to BIC/FTC/TAF: Virologic Outcomes at Wk 48 Outcome at Wk 48, n (%) Switch to BIC/FTC/TAF (n = 282) Continued DTG/ABC/3TC (n = 281) Treatment Difference, % (95.002% CI) No treatment-emergent resistance detected in any pt P Value HIV-1 RNA 50 copies/ml 3 (1.1) 1 (0.4) 0.7 (-1.0 to 2.8).62 HIV-1 RNA < 50 copies/ml 264 (93.6) 267 (95) NR.59 No virologic data 15 (5.3) 13 (4.6) NR NR Molina J-M, et al. CROI Abstract O22. Slide credit: clinicaloptions.com

86 Switch From Suppressive DTG/ABC/3TC to BIC/FTC/TAF: Safety Outcomes at Wk 48 Outcome, n (%) BIC/FTC/TAF (n = 282) *Fischer exact test P =.01. Molina J-M, et al. CROI Abstract O22. DTG/ABC/3TC (n = 281) Any TRAE 23 (8)* 44 (16)* TRAE in 1% of pts Headache Abnormal dreams Flatulence Nausea Diarrhea Fatigue Insomnia 7 (3) 1 (< 1) (< 1) 1 (< 1) 0 8 (3) 5 (2) 5 (2) 5 (2) 4 (1) 3 (1) 3 (1) Any gr 3/4 lab abnormality 47 (17) 32 (11) Gr 3/4 lab abnormalities in 2% of pts LDL elevation Increased amylase ALT elevation CK elevation Fasting hyperglycemia 14 (5) 7 (2) 6 (2) 6 (2) 6 (2) 13 (5) (2) 2 (< 1) Median egfr CG change from BL: BIC arm, 1.0 ml/min; DTG arm, -1.8 ml/min; P <.001 No significance differences between arms in changes from BL for proteinuria levels, spine and hip BMD No significant differences in changes for fasting lipids, except triglycerides Median change for triglycerides: BIC arm, -5 mg/dl; DTG arm, +3 mg/dl; P =.028 Slide credit: clinicaloptions.com

87 Switch From Suppressive PI- or INSTI-Based ART to BIC/FTC/TAF in Women Open-label, randomized, active-controlled phase III trial Primary endpoint: Wk 48 HIV-1 RNA 50 c/ml (FDA snapshot; noninferior. margin 4%) Pts from Uganda (27%), Russia (24%), Thailand (22%), US (15%), Dominican Republic (12%) Wk 48 Pts with HIV-1 RNA < 50 c/ml for 6 mos on EVG/COBI/FTC/(TAF or TDF) or ATV + RTV + FTC/TDF; CrCl 50 ml/min (N = 470) BIC/FTC/TAF* (n = 234) Continued Baseline Regimen (n = 236) Median baseline values: age, yrs; CD4+ cell count, cells/mm 3 Regimen at randomization: EVG/COBI/FTC/TAF, 53%; EVG/COBI/FTC/TDF, 42%; ATV + RTV + FTC/TDF, 5% *BIC/FTC/TAF 50/200/25 mg PO QD. Kityo C, et al. CROI Abstract 500. Slide credit: clinicaloptions.com

88 Switch From Suppressive ART to BIC/FTC/TAF in Women: Wk 48 Efficacy and Safety Outcomes Outcome at Wk 48, n (%) No treatment-emergent resistance detected in BIC/FTC/TAF arm No d/c for AE in either arm Switch to BIC/FTC/TAF (n = 234) Continued BL Regimen (n = 236) Similar grade 3/4 AE rates, changes in egfr CG and most lipid measurements between treatment arms Treatment Difference, % (95.001% CI) HIV-1 RNA 50 copies/ml 4 (2) 4 (2) 0.0 (-2.9 to 2.9) HIV-1 RNA < 50 copies/ml 224 (96) 225 (95) NR No virologic data 6 (3) 7 (3) NR Median change in TG: BIC/FTC/TAF, -10%; baseline ART, +4%; P <.001 Kityo C, et al. CROI Abstract 500. Slide credit: clinicaloptions.com

89 London 90% 97% 97% Diagnosed On treatment Undetectable * *VL <200 c/ml. Public Health England, 2016.

90 Quality of life frontier: The 4 th 90 Enhancing engagement with care Avoiding side effects and comorbidity 90% 97% 97%? Diagnosed On treatment Undetectable 4 th Lazarus JV, et al. BMC Med 2016;14:94.

91 volledige hiv cascade PLWHIV beyond : - (less) adverse events - comorbidities, aging - quality of life Dx cart <100 QoL

92 What else could we do to stop disengagement from care? Addressing stigma Different modalities (longer acting) More peer mentoring and navigation Behavioral interventions: App and SMS-based reminders Behavioral prompts

Proportion of patients (%) First-line ART Determinants of efficacy by FDA snapshot 100 80 VL <50 c/ml driven by: Baseline viral load Barrier to resistance 60 40 20 No data in window: Tolerability

93 Proportion of patients (%) First-line ART Determinants of efficacy by FDA snapshot VL <50 c/ml driven by: Baseline viral load Barrier to resistance No data in window: Tolerability (discontinuations) Safety (withdrawals) LTFU/withdrawals 0 Virologic response (VL <50 c/ml) VL 50 c/ml No data in window FDA, The Food and Drug Administration; LTFU, loss to follow-up; VL, viral load.

Disclosures (last 12 months)

HIV Research What s in the Pipeline? Samir K. Gupta, MD, MS Division of Infectious Diseases Indiana University School of Medicine Disclosures (last 12 months) Independent research grant funding by NIH/NHLBI,