Reduced drug regimens

Transcription

1 Reduced drug regimens Andrea De Luca MD Dipartimento di Biotecnologie Mediche, Università di Siena Department of Internal Medicine, University Hospital, Siena, Italy

2 Conflicts of interest Research grants from: ViiV Healthcare Gilead (Fellowship Program) Merck, Sharp and Dohme Paid consultancies: ViiV Healthcare Gilead Sciences Merck, Sharp and Dohme Janssen Abbvie

3 Outline Regimens with 2 drugs Use in clinical practice Efficacy in RCT and prospective or cohort studies First-line Switch in virosuppressed individuals Long term follow up Effect of previous resistance and emerging resistance on 2 drugs (forgiveness?) Other outcomes: HIV DNA, inflammation, CNS

4 June 2017 Report 100% 90% 80% 70% Proportion of patients with a VL<=80 copies/ml at 12 months from starting their first ART regimen by calendar year of initiation 85,5% 88,8% 90,5% 88,9% 88,1% 89,9% 91,2% 94,3% 95,4% 95,7% 83,1% 75,0% 78,1% 80,5% 77,1% 60% 50% 40% 30% 20% 10% 58,1% 52,5% 43,6% 38,3% 17,0% 0%

5 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Proportion of mono/dual PI therapies according to calendar period of starting for 2017, first 6 months 0,8% 1,7% 5,2% 3,2% 6,4% 4,2% 8,9% 1,7% Dual Mono June 2017 Report

6 Most used DRV-containing mono/dual therapies DRV/r DRV/r,RAL 3TC,DRV/r ETV,DRV/r DRV/r,DGV DRV,cob DRV/r,MRV 3TC,DRV,cob other Most used ATV-containing mono/dual therapies TC,ATV/r ATV/r ATV/r,RAL ATV,RAL other June 2017 Report

7 DGV-containing dual therapies TC,DGV DRV/r,DGV RPV,DGV DRV,DGV,cob ATV,DGV other June 2017 Report

8 3,7% 0,50% 4,4% 7,8% 4,42% 6,2% 7,3% 13,0% 9,7% 16,7% 20,6% 15,56% 8,7% 16,5% 11,5% 11,93% 9,2% 18,9% 11,2% 7,91% 5,2% 6,8% 25,7% 22,1% 21,4% 21,22% 21,8% 25,24% 40,9% 36,4% 44,9% 51,4% 57,1% 52,7% 61,2% 70% Reasons for stopping at least one drug of the first ART regimen within 1 year, according to calendar period of starting N = therapy interruptions per period 60% 50% 40% 30% 20% 10% 0% (N=602) (N=294) (N=257) (N=218) (N=455) (N=735) (N=206) FAILURE OTHER PATIENT'S DECISION SIMPLIFICATION TOXICITY for 2017, first 6 months June 2017 Report

9 Dual RCT in treatment naive: unsuccessful studies DRV/r + MVC inferior to 2NA + DRV/r Well powered ATV/r + MVC inferior to 2NA + ATV/r Small, limited power ATV/r + RAL inferior to ATV/r + 2NA More jaundice, InSTI resistance selection

10 Study Maintenance dual ART: completed prospective trials Previous regimen Study regimen control n Main Efficacy outcome Benefits/Harms ATLAS-M ATV/r+2NA ATV/r+3TC ATV/r+2NA 266 Non-inferior (superior) egfr, bone, AE/lipids SALT Any triple ATV/r+3TC ATV/r+2NA 273 Non-inferior Less AE/lipids OLE LPV/r+2NA LPV/r+3TC LPV/r+2NA 250 Non-inferior No/lipids DUAL DRV/r+2NA DRV/r+3TC DRV/r+2NA 257 Non-inferior MOBIDIP bpi+2na bpi+3tc bpi 265 Dual>mono (VF 48w 3% vs 24.8%) All had previous M184V PROBE PI/r+2NA DRV/r+RPV continue 60 Non-Inferior Bone, immune activation/lipids Multineka LPV/r+2NA LPV/r+NVP LPV/r+2NA 67 Non-inferior GUSTA Any triple DRV/r+MVC qd cont 133 Inferior AE, Bone, AP MARCH PI/r+2NA PI/r+MVC bid 2NRTI+MVC bid cont 395 PI/r+MVC inferior

11 Maintenance dual ART: completed prospective trials Study Previous regimen Study regimen LATTE CAB+2NA CAB+RPV IM EFV+2NA 243 Non-inferior LATTE-2 CAB (oral)+abc/3t C CAB+RPV IM q4w or q8w control n Main Efficacy outcome Benefits/Harms CAB (oral)+abc/ 3TC 309 Non-inferior Patients satisfaction/isr SWORD Any triple DTG+RPV continue 1024 Non-inferior Improved BMD and bone turnover markers SPARE LPV+TVD DRV/r+RAL LPV+TVD 58 egfr urinary b2m improved Harness Any triple ATV/r+RAL ATV/r+2NA 109 Inferior KITE 2NA+X LPV/r+RAL continue 60 Non-inferior no/lipids ANRS 167 LAMIDOL DOLULAM Triple (81% bpi, 26% RAL) 2NA+X DTG+3TC no % success w48 (1 PDVF) Some excluded after induction (VF, tox) DTG+3TC no 27 2 years: no VF 63% had historical RNA or DNA with M184I/V ASPIRE Triple DTG+3TC continue 89 W48 DT 91%, TT 89%; VF 1 each arm (no resistance) Lipids and renal function similar

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13 Favors ATV/rit+2 NRTI Favors ATV/rit+3TC Efficacy in ATLAS-M: 96 weeks 12% -12% Fabbiani M JAC 2017

14 Evolution of renal function

15 Bone outcomes at 96 weeks Changes in BMD at 96W (%) Dual arm TT arm Lumbar Spine Total Hip Femoral neck n=73 DT arm: 41 TT arm: 32 p= ns p= ns p= Bone turnover biomarkers (%) Dual arm TT arm p= ns p= ns p= ns p= ns PTH Vitamin D Osteocalcin FAO ,

16 Antiretroviral resistance selected at failure in HIV+ treated with triple or dual regimens Calvez V, EACS 2017

17 Calvez V, EACS 2017

18 Calvez V, EACS 2017

19 Calvez V, EACS 2017

20 Calvez V, EACS 2017

21 Calvez V, EACS 2017

22 Probability of experiencing virological rebound Drug resistance and virological rebound with DRV or ATV/r+3TC 1.0 No. of CDR classes: None p=0.002 by log-rank test for trend 20% 7.4% 4.8% 4.2% 33.3% 11.8% 4.8% 4.2% Time (months) No. at risk CDR: cumulative drug resistance. ID Patient Cumulative RAMs prior to switch RAMs at 3TC+ATV/r failure PI NRTI NNRTI PI NRTI NNRTI GEV- GE03038 M46I, I54V, L76V, V82F A62V, K65R, K70R, V75I, Y115F, F116Y, Q151M, M184V Y188L, G190A M46I, I54V, L76V, V82F A62V, K65R, K70R, V75I, Y115F, F116Y, Q151M, M184V Y188L, G190A MOV-MO None M41L, D67N, K70R, T215Y, K219Q K101E, E138Q, G190A V32I, M46L, I50L, V82A M41L, D67N, K70R, M184V, T215Y, K219Q K101E, G190A Di Carlo D, ICAR 2017 (submitted) Boldface represent acquired mutations compared to cumulative RAMs prior to switch. /r boosted ritonavir. 3TC: lamivudine. ATV: atazanavir. NNRTI: non-nucleoside reverse transcriptase inhibitor. NRTI: nucleos(t)ide reverse transcriptase inhibitor. PI: protease inhibitor. RAMs: resistance associated mutations.

23 Galizzi N 16 EMHH 2018

24 Galizzi N 16 EMHH 2018

25 HIV-1 RNA (copies/ml) ACTG A5353: HIV-1 RNA Levels and DTG Concentration in Pts Experiencing PDVF Pt 1 BL HIV-1 RNA > 100,000 copies/ml Pt 2 BL HIV-1 RNA 100,000 copies/ml Off DTG Pt 3 BL HIV-1 RNA 100,000 copies/ml Off DTG 1,000, ,000 10, Study Wk None ,000, ,000 10, None M184V M184V R263RK Study Wk ,000, ,000 10, Study Wk V DTG Concentration (ng/ml) HIV-1 RNA (copies/ml) DTG concentration (ng/ml) HIV-1 RNA < limit of detection No detectable DTG Taiwo BO, et al. IAS Abstract MOAB0107LB. Reproduced with permission. Slide credit: clinicaloptions.com

26 M184V and Switch to 3TC-Based Dual ART Gagliardini R Open Forum Infect Dis 2018

27 Virological outcomes on dual therapies Overall incidence of VF: 2.35 per 100 PYFU 13 over 572 PYFU in M184V- pts (2.27 per 100 PYFU) 4 over 153 PYFU in M184V+ pts (2.63 per 100 PYFU) 3 DRV/r+3TC, 1 ATV/r+3TC Median follow-up: 1.2 years (IQR ) Estimated probability of remaining free from VF with dual therapy at 3 years M184V- 92.5% (95% CI 87.2; 97.8) M184V+ 92.5% (95% CI 85.0; 99.9) p=0.824 Virological blips occurred in 29/352 (8%) M184V- pts and 15/84 (18%) M184V+ (p=0.009). Gagliardini R 15th EMHH, 2017

28 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

29 M184V and Switch to 3TC-Based Dual ART: Predictors of VF: GSS of the 2 nd drug better predicts VF as M184V Implications for DTG+3TC? Gagliardini R Open Forum Infect Dis 2018

30 ANRS 167 LAMIDOL DTG + 3TC as Maintenance Therapy Joly V, et al. CROI Seattle, WA. Poster #458 Inclusion Criteria Current: 2 NRTIs + either NNRTI, PI, or INSTI Maximum of 2 previous ART modifications (simplification or one tolerability switch) Suppressed <50 c/ml for 2 years with no blips in previous 6 months * Wild type virus CD4 nadir >200 cells/mm 3 INDUCTION DTG + 2 NRTIs (n=110) MAINTENANCE DTG + 3TC (n=104) Baseline Week 8 Week 48 & 56 Outcomes INDUCTION: 95% (104/110) eligible for dual therapy MAINTENANCE: 97% (101/104) remained suppressed 1 virologic failure: W4 with VL 84 c/ml 1 therapeutic failure: W40 with blip VL 59 c/ml 1 lost to follow-up: W32 Switching to DTG+3TC maintained virologic suppression in patients without history of virologic failure >18 years Normal labs & HBsAg negative * Subjects were on current ART for a median of 4 years (range: ) 6 subjects were ineligible for Phase 2: 3 with detectable VL and 3 with AEs (1 serious AE of suicide ideation)

31 N= 216 pts switching To DTG+3TC - All switching from TT - No previous M184V - HBsAg neg - No VF over a - Median of 2yrs Maggiolo F ICAR 2018

32 VF with DTG+3TC in switch (Odoacre) 206 patients median follow up of 12.8 months: 5 virological failures over PYFU (2.3 VF per 100 PYFU). Estimated probabilities of maintaining virological suppression 48 weeks 98.2% (95% CI, 96.0%-100%) 96 weeks 95.1% (95%CI 90.4%-99.8%) Peak HIV-1 RNA 5x10 5 copies/ml: 7.8 VF per 100 PYFU: Probabilities of virological suppression in subgroup 48 weeks 95.2% (95%CI 86.2%-100.0%) 96 weeks 86.6% (95%CI 68.4%-100.0%) (vs <5x10 5 copies/ml p=0.049) lack of adherence 2 of 5 1 with a long history of disease and cart had single viral rebound and achieved immediate re-suppression with the same regimen (no resistance mutations at GRT); 1 patient had long history of HIV disease and past AIDS presented 2 consecutive viral blips and had a treatment change to ABC/3TC+DTG, with immediate viral control. 1 highly-experienced patient (previous M184V) had 2consecutive viral blips and was switched to atazanavir 200 mg BID plus dolutegravir 50 mg BID, with viral control. Borghetti A HIV Medicine 2018 and unpublished

33 NRTI or NNRTI required in dual? NRTI: strong evidence of residual activity, especially with PI, but also with DTG (Dawning trial) PK properties of NRTIs NNRTI work only if fully active

34 The Lancet Infectious Diseases , 47-57DOI: ( /S (17) ) Paton NI, et al. Lancet HIV. 2017;4:e341-e348. EARNEST: Second-line LPV/RTV Figure in 2 Patients With Virologic Failure: 144wks follow-up Open label, 14 African sites, all pts failing 2NRTI+NNRTI Wk 144: PI+RAL vs PI +NRTI -4.9% (-10.2; +0.3) (NOT non-inferior)

35 HIV DNA changes at 96w: ATLAS-M blood-associated HIV-DNA levels quantified at baseline and at week 96 in a subset of 140 patients. Mean baseline HIV-DNA levels (log 10 copies/10 6 leukocytes) were comparable in atazanavir/ritonavir+lamivudine (2.42, 95% CI ) versus atazanavir/ritonavir+2nrti arm (2.37, 95% CI )(p=0.570). At 96 weeks, a significant decrease from baseline in HIV-DNA was observed in both arms: (95% CI -0.23/-0.07, p<0.001) in the dual therapy arm versus (95% CI -0.27/-0.08, p<0.001) in the control arm, without significant differences between the two arms (p=0.703). Fabbiani M JAC 2017

36 Neurocognitive performance in ATLAS-M: 96 weeks 107 patients tested (40.2%).56 and 51 in study and control arm At baseline, patients in the two arms did not differ for the main characteristics and showed a comparable proportion of cognitive impairment (10.7% in the atazanavir/ritonavir+lamivudine versus 21.7% in the atazanavir/ritonavir+2nrti arm, all with a profile of asymptomatic cognitive impairment; 16 p=0.185). At 96 weeks, the two groups confirmed no difference in the prevalence of cognitive impairment (14.3% versus 13.7%, respectively, p=1.000). NO SIGNIFICANT CHANGE FROM BASELINE IN EITHER GROUP Fabbiani M JAC 2017

37 Longitudinal comparison of biomarkers of inflammation, coagulation and monocyte activation in Atlas-M No significant change in CRP, IL-6 scd14 and d-dimer within and between arms Similar results observed in SWORD Belmonti S et al JAC 2018; Llibre JM Lancet 2018

38 Dual therapies: considerations As of today, most solid evidence of efficacy in maintenance therapy PI/r+3TC: no/rare resistance selection (HIV DNA, inflammation markers, neurocognitive function OK) DTG+RPV: rare resistance selection (inflammation markers OK) NRTI or NNRTI required Caveat: PI/r tolerability? Toxicity benefits of dual vs triple: Bone and renal, due to TDF discontinuation TAF and the need of dual

39 Dual therapies: considerations Reduced costs Not for all dual therapies DTG + 3TC new results from phase III RCT expected Naive (Gemini), maintenance (Tango) Beyond efficacy, tolerability and costs will be relevant Previous M184V? Resistance selection? Candidates to dual therapy should not have resistance/failure with drugs/classes used in the dual combination Regimens forgiveness still has to be elucidated