Two Drug Regimens Pros and Cons. Jürgen Rockstroh Department of Medicine I University Hospital Bonn, Bonn, Germany

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1 Two Drug Regimens Pros and Cons Jürgen Rockstroh Department of Medicine I University Hospital Bonn, Bonn, Germany HIV Clinical Forum, Moscow, Russia, Friday 23 rd November 2018

2 Conflict of Interest: JKR Honoraria for lectures and/or consultancies from Abbott, AbbVie, Gilead, Hexal, Janssen, Merck, and ViiV. Research grants from Dt. Leberstiftung, DZIF, NEAT ID.

3 Is life-long Triple Therapy Needed for Every Patient? Life-long antiretroviral therapy Goals of Antiretroviral Therapy Maintain viral suppression without jeopardizing future treatment options Enhance tolerability and decrease short- or long-term toxicity Simplify by reducing pill burden and dosing frequency Prevent or mitigate interactions Eliminate food or fluid requirements Potential Benefits of Dual Therapy Avoid long-term toxicities Preserve long-term ART options Reduce costs May be easier for producing FDC and smaller tablet size 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at Accessed 02/ Achhra AC et al. Lancet HIV 2016; 3: e

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5 Evolution of Dual Therapy: Major Clinical Studies Including Dual Regimens Initial Therapy DMP ACTG NEAT0014 GARDEL 5 MODERN 6 PADDLE 11 ANDES 13 GEMINI 1 and ACTG OLE 7, SALT 8 Maintenance Therapy DUAL-GESIDA 9 SWORD Havir D et al. N Engl J Med. 1998: Staszewski S et al. N Engl J Med. 1999: Riddler SA et al. N Engl J Med 2008;358: Raffi F et al. Lancet. 2014: Cahn P et al. Lancet Infect Dis. 2014: Stellbrink HJ et al. AIDS 2016: Arribas J, et al. Lancet Infect Dis. 2015: Perez-Molina JA, et al. Lancet Infect Dis. 2015: Pulido F et al. Clin Infect Dis Liibre JM et al. Lancet Cahn P et al. J Int AIDS Soc Cahn P et al. Lancet Figueroa MI et al. CROI

6 Two Drug Regimens Pros and Cons Initial therapy Seite 6

7 Evolution of Dual Therapy: Outcomes of Dual Regimens in Initial Therapy ACTG DMP NEAT001 3 GARDEL 4 MODERN Comparators DMP ACTG NEAT001 3 GARDEL 4 MODERN 5 EFV+IDV vs. 2 NRTIs + EFV or IDV EFV+LPV/r vs. 2 NRTIs + EFV or LPV/r RAL+DRV/r vs. DRV/r+2 NRTIs Efficacy Inferior Non-Inferior Non-Inferior in CD4>200 LPV/r+3TC vs. LPV/r + 2 NRTIs Non-Inferior MVC + DRV/r vs. DRV/r + 2 NRTIs Tolerability No differences Superior No differences Inferior Development of Resistance More resistance in DL 16% vs. 9% and 6% Dual arm: M184V (n=2) 1. Staszewski S et al. N Engl J Med. 1999: Riddler SA et al. N Engl J Med 2008;358: Raffi F et al. Lancet. 2014: Cahn P et al. Lancet Infect Dis. 2014: Stellbrink HJ et al. AIDS 2016:

8 ANDES Study - DRV/r + 3TC Vs DRV/r +TDF/3TC for HIV-1 Treatment-Naïve Patients: Week 48 Results Demographics at Screening Global (n=145) 33.1± ( ) Triple Therapy (n=70) 32.5± (26-38) Double Therapy (n=75) 33.7± (24-92) Males 131 (91%) 61 (88%) 70 (93%) Hispanic/Latino 102 (71%) 49 (71%) 53 (71%) MSM/Bisexual 101 (73%) 48 (71%) 53 (76%) CDC Stage B 11 (8%) 5 (7%) 6 (8%) Viral Load (log) 4.5 ( ) 4.5 ( ) 4.6 ( ) CD4 Count 383 ( ) ( ) 419 ( ) CD4 % 19 (14-25) 19 (14-25) 19 (14-25) VL > c/ml (Baseline) 35 (24%) 15 (22%) 20 (27%) Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, Abst Bacon O, et al. 25th CROI; Boston, MA; March 4-7, Abst. 93.

9 ANDES Study: Proportion with HIV-RNA < 50 Copies/mL and Safety Global Triple Therapy Double Therapy Difference Primary Outcome: VL<50 c/ml at Week 48 ITT Snapshot, (n=145) 136 (94%) 66 (94%) 70 (93%) -1.0% (-7.5; 5.6%) ITT Snapshot, Baseline VL>100,00 c/ml (n=35) 32 (91%) 12 (92%) 20 (91%) -1.4% (-17.2; 14.4%) Observed (n=140) 136 (99%) 66 (99%) 70 (100%) -1.5% (-0.9; 3.9%) Adverse Events Rash 7% 8% Gastrointestinal 14% 7% Total Cholesterol (Change from BSL) 4% 19%; p:0.01 LDL-Cholesterol 6% 14% Triglycerides 14% 25% Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, Abst. 489.

10 GEMINI-1 & 2: study design Identically designed, randomized, double-blind, parallel-group, multicenter, noninferiority studies Screening (~28 days) 1:1 Double-blind phase Open-label phase Continuation phase ART-naive adults VL ,000 c/ml DTG + 3TC (N=716) DTG + TDF/FTC (N=717) DTG + 3TC D1 Eligibility criteria 10 days of prior ART No evidence of pre-existing viral resistance based on presence of any major resistance-associated mutation No HBV infection or need for HCV therapy W24 W48 Primary endpoint at Week 48: participants with HIV-1 RNA <50 c/ml (ITT E snapshot) a Orkin et al. HIV Glasgow 2018; Glasgow, UK. Poster P021. W96 W144 Countries Argentina Canada Italy Netherlands Portugal South Africa Taiwan Australia Belgium France Germany Republic of Korea Mexico Peru Poland Romania Russian Federation Spain Switzerland United Kingdom United States Baseline stratification factors: plasma HIV-1 RNA ( 100,000 vs >100,000 c/ml) CD4+ cell count ( 200 vs >200 cells/mm 3 ) a 10% noninferiority margin for individual studies.

11 Demographics and Baseline Characteristics: Pooled ITT E Population Characteristic DTG + 3TC (N=716) DTG + TDF/FTC (N=717) Age, median (range), y 32.0 (18-72) 33.0 (18-70) Female, n (%) 113 (16) 98 (14) Race, n (%) African heritage Asian White Other HIV-1 RNA, median (range), log 10 c/ml >100,000, n (%) CD4+ cell count, median (range), cells/mm 3 200, n (%) 99 (14) 71 (10) 480 (67) 66 (9) 4.43 ( ) 140 (20) ( ) 63 (9) 76 (11) 72 (10) 497 (69) 72 (10) 4.46 ( ) 153 (21) ( ) 55 (8) Orkin et al. HIV Glasgow 2018; Glasgow, UK. Poster P021.

12 HIV-1 RNA <50 c/ml, % GEMINI 1 and 2: Snapshot Outcomes at Week 48 Virologic outcome Adjusted treatment difference (95% CI) a GEMINI-1 DTG + 3TC (N=356) DTG + TDF/FTC (N=358) GEMINI-2 DTG + 3TC (N=360) DTG + TDF/FTC (N=359) DTG DTG + TDF/FTC + TDF/FTC DTG + 3TC 60 GEMINI GEMINI Virologic success Virologic nonresponse No virologic data Percentage-point difference No resistance development in both study arms up to weeek 48 Cahn P, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0106LB.

13 GEMINI studies subgroup analyses: Baseline characteristics Subgroup DTG + 3TC n/n (%) DTG + TDF/FTC n/n (%) Variable Overall 655/716 (91) 669/717 (93) Age, y <35 386/420 (92) 381/408 (93) 35 to <50 211/231 (91) 216/229 (94) 50 58/65 (89) 72/80 (90) Sex Female 100/113 (88) 89/98 (91) Male 555/603 (92) 580/619 (94) Race, n (%) White 447/480 (93) 471/497(95) African heritage 83/99 (84) 64/76 (84) Asian 67/71 (94) 68/72 (94) Other 58/66 (88) 66/72 (92) Baseline HIV-1 RNA, c/ml 100, /576(91) 531/564 (94) >100, /140 (92) 138/153 (90) >250,000 45/51 (88) 41/46 (89) >400,000 16/18 (89) 20/24 (83) Baseline CD4+cell /63 (79) 51/55 (93) count, cells/mm 3 > /653 (93) 618/662 (93) -13,4 3-Drug regimen -1,5-3,0-0,8-2,3-1,7-1,6-0,4-0,1-3,8-0,9-1,7-2,8-0,7 2-Drug regimen 1,9 5, Treatment difference, % (95% CI) Orkin C, et al. HIV Glasgow; October 2018; Glasgow, UK; Abst. P021.

14 Snapshot non-response: participants with Baseline CD Participant DTG + 3TC Snapshot outcome (Week 48) Clinical Reason for study DC Study day of DC Last study VL, c/ml 1 VL 50 c/ml NA: continued in study NA 50 a,b 2 VL 50 c/ml NA: continued in study NA <50 a 3 VL 50 c/ml NA: continued in study NA <50 a 4 VL 50 c/ml Protocol-defined virologic withdrawal VL 50 c/ml NA: Unplanned change in ART NA 50 a,b 10 VL 50 c/ml PV: randomized in error c VL 50 c/ml Lost to follow-up No virologic data AE: pulmonary TB 206 <50 6 No virologic data AE: cerebral chagoma ,564 d 7 No virologic data Treatment for HCV infection 165 <50 8 No virologic data Withdrew consent 115 <50 11 No virologic data PV: randomized in error e 28 1,848,435 f 13 No virologic data Lost to follow-up 100 <50 DTG + TDF/FTC 14 VL 50 c/ml NA: continued in study NA <50 a 16 VL 50 c/ml Investigator discretion: incarceration No virologic data Withdrew consent 342 <50 17 No virologic data Lost to follow-up 175 <50 DC, discontinuation; NA, not applicable; PV, protocol violation, a VL results from Week 60 shown for participants who continued the study beyond Week 48. b Value not provided due to potential for unblinding. c Enrolled with HBV coinfection. d Participant had discontinued study treatment prior to study DC. e Enrolled with Screening VL of >500,000 c/ml. f VL result available from Day 1 only. Orkin et al. HIV Glasgow 2018; Glasgow, UK. Poster P021.

15 Primary Endpoint NEAT 001 By BL Characteristics Overall analysis: RAL + DRV/r non-inferior to TDF/FTC + DRV/r However, inferior in patients < 200 cells/µl RAL + DRV/r TDF/FTC + DRV/r Overall n = % 13.8 % Baseline HIV-1 RNA < 100,000 copies/ml n = % 7.3 % > 100,000 copies/ml n = % 27.3 % No significant difference p = 0.10* Baseline CD4 + < 200 cells/mm 3 n = % 20.9 % > 200 cells/mm 3 n = % Significant difference 12.3 % p = 0.010* Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted * Interaction Test Raffi F et al. Lancet 2014

16 DHHS GUIDELINES UPDATE - October 2018 Most People with HIV BIC/TAF/FTC DTG/ABC/3TC DTG-TFV/FTC RAL-TFV/FTC Certain Clinical Situations EVG/c/TFV/FTC RAL-ABC/3TC DRV/c(r)/TFV/FTC ATV/c(r)/TFV/FTC DRV/c(r)-ABC/3TC DOR/TDF/3TC or DOR-TAF/FTC EFV/TDF/FTC(3TC), EFV-TAF/FTC RPV/TFV/FTC When ABC, TAF, and TDF Cannot be Used or Are Not Optimal DTG+3TC DRV/r + RAL BID DRV/r + 3TC

17 EACS GUIDELINES UPDATE OCTOBER 2018 Recommended regimens (preferred) DTG/ABC/3TC DTG-TFV/FTC BIC/TAF/FTC RAL qd/bid -TFV/FTC Recommended regimens RPV/TFV/FTC DRV/c(r)/TFV/FTC EFV/TDF/FTC(3TC), EFV-TAF/FTC Alternative RAL-ABC/3TC EVG/c/TFV/FTC ABC/3TC-EFV TDF/FTC/EFV ABC/3TC-ATV/c(r) ABC/3TC-DRV/c(r) TFV/FTC-ATV/c(r) Other DTG+3TC DRV/r(c)+ RAL BID

18 Two Drug Regimens Pros and Cons: initial therapy PROS Cost Avoid toxicities Smaller tablet potentially CONS Not enough data in advanced patients No data in patients with viral load > copies/ml Not recommendable in test and treat strategy Toxicity of modern integrase and TAF based therapies is very low No effective HBV therapy or HBV prevention No FDC of Dolutegravir/3TC available yet No FDC of Darunavir/r/3TC available Not yet recommended as initial treatment by guidelines Seite 18

19 Two Drug Regimens Pros and Cons Maintenance therapy Seite 19

20 Evolution of Dual Therapy: Outcomes of Dual Regimens in Maintenance Therapy Comparators ACTG343 1 OLE 2 SALT 3 DUAL-GESIDA 4 SWORD 5 IDV + AZT/3TC vs. IDV vs. AZT/3TC LPV/r + 3TC vs. LPV/r + 2 NRTIs ATV/r + 3TC vs. ATV/r + 2 NRTIs DRV/r + 3TC vs. DRV/r + 2 NRTIs DTG + RPV vs. Triple ART Efficacy Inferior Non-Inferior Non-Inferior Non-Inferior Non-Inferior Tolerability No differences Less discontinuations 2% vs. 7% (p=0.047) No differences No differences Development of Resistance No differences No differences No differences No differences ACTG 343 OLE, SALT DUAL-GESIDA SWORD 1. Havir D et al. N Engl J Med. 1998: Pulido F et al. Clin Infect Dis Arribasl J, et al. Lancet Infect Dis. 2015: Liibre JM et al. Lancet Perez-Molina JA, et al. Lancet Infect Dis. 2015:

21 SWORD study: Dolutegravir + Rilpivirine for Maintenance of Suppression Phase III, Randomized, Multicenter, Open-label, Parallel-Group, Non-Inferiority Studies Screening Early Switch Phase a Late Switch Phase Continuation Phase VL <50 c/ml on INI, NNRTI, or PI + 2 NRTIs 1:1 DTG + RPV (N=513) CAR (N=511) DTG + RPV DTG + RPV Day 1 Week 52 Week 148 Inclusion Criteria On stable CAR 6 months before screening 1 st or 2 nd ART with no change in prior regimen due to VF Confirmed HIV-1RNA <50 c/ml during the 12 months before screening Primary endpoints at 48 weeks: subjects with VL <50 c/ml (ITT-E snapshot) b Countries Argentina France Russia United States Australia Germany Spain Belgium Italy Taiwan Canada Netherlands United Kingdom a. DTG + RPV once daily or 2 NRTIs + INI/PI/NNRTI (CAR). b. 90% power based on 10% non-inferiority margin (estimated response rate =87%). Aboud M, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. THPEB047

22 SWORD 1&2: Week 48 and Week 100 Snapshot Outcomes AE, adverse event; DTG, dolutegravir; RPV, rilpivirine. DTG+ RPV N=513 n (%) Week 48 1 Early-switch group DTG + RPV N=513 n (%) Week 100 Late-switch group DTG + RPV N=477 n (%) Week 100 Virologic success 486 (95) 456 (89) 444 (93) Virologic nonresponse 3 (<1) 13 (3) 10 (2) Data in window, not <50 copies/ml 0 5 (<1) 3 (<1) Discontinued for lack of efficacy 2 (<1) 7 (1) 3 (<1) Discontinued while not <50 copies per ml 1 (<1) 1 (<1) 0 Change in ART (<1) No virologic data 24 (5) 44 (9) 23 (5) Discontinued because of AE or death 17 (3) 27 (5) 11 (2) Discontinued for other reasons 7 (1) 17 (3) 9 (2) Missing data during window but on study (<1) Through 100 weeks of treatment, DTG + RPV continued to be efficacious in the early-switch group Virologic efficacy in the late-switch group at Week 100 was comparable to that of the earlyswitch group at Week Llibre et al. Lancet. 2018;391: and Aboud et al. IAS 2018 Poster THPEB047

23 DTG + RPV: Low Rates of CVW Through Week 100 a Shading represents participants with treatment-emergent NNRTI resistance associated mutations. b Underlined value denotes viral load when participant met virologic withdrawal. c HIV-1 baseline resistance testing was performed on integrated HIV-1 proviral DNA using GenoSure Archive assay (Monogram Biosciences, South San Francisco, CA). Onstudy resistance testing used standard plasma-based genotypic and phenotypic resistance testing. d Participants in the late-switch group. e Resistance testing not performed because of low viral load. CAR, current antiretroviral regimen; CVW, confirmed virologic withdrawal; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor. Aboud et al. IAS 2018 Poster THPEB047

24 No significant changes to residual viremia after switch to DTG and 3TC Randomization 1:1» Baseline Characteristics:» Male: 88%» Age: 47 years» White/black/Hispanic: 60%/38%/15%» CD4: 680 cells/µl» Time on ART: 5.7 years» Current ART: NNRTI (30%), PI/r (33%), INSTI (37%) FTC/TDF (86%), ABC/3TC (14%) Switch to DTG 50 mg + 3TC 300 mg qd (n=44) Continue Triple Therapy (n=45) Week Primary Endpoint Li J, et al. HIV Glasgow; October 2018; Glasgow, UK; Abst. O145.

25 Patients (%) Virologic Outcomes (FDA Snapshot) 100 Difference (%): 2.1 (-11.2, 15.3) 93% 91% Difference (%): 2.0 (-12.6, 16.5) 91% 89% % 0% 2% 2% Week 24 Week 48 Virologic Failure Week 24 Week 48 HIV RNA <50 Copies/mL Dolutegravir + lamivudine (n=44) Continue triple therapy (n=45) Li J, et al. HIV Glasgow; October 2018; Glasgow, UK; Abst. O145.

26 copies/ml Study Results» Integrase Single Copy Assay (isca) with a 0.5 HIV-1 RNA copies/ml limit of detection» At baseline, mean residual viremia did not differ between arms 4.9 c/ml (DTG+3TC) vs. 5.3 c/ml (cart) diff = -0.5 c/ml, 95% CI [-3.8, 2.8], p= HIV viral load by isca by Treatment Arm at Baseline, 24 and 48 Weeks Treatment DTG+3TC ART study week Li J, et al. HIV Glasgow; October 2018; Glasgow, UK; Abst. O145.

27 Two Drug Regimens Pros and Cons: Maintenanace therapy PROS Cost (for some combinations) Avoid toxicities Smaller tablet potentially May allow simplification in historic patients with prior NRTI and efavirenz or PI/r failure CONS Cost (for some combinations) Toxicity of modern integrase and TAF based therapies is very low Risk for resistance development over time? Change in genetic barrier? No effective HBV therapy or HBV prevention Not all dual regimens available as FDC yet Seite 27

28 Two Drug Regimens Pros and Cons General considerations Seite 28

29 EACS 9.1: Indications for ART Switch in Suppressed Patients 1. Documented toxicity caused by one or more of the antiretrovirals included in the regimen. Examples of these reactive switches: lipoatrophy (d4t, AZT), central nervous system adverse events (EFV), diarrhoea (PI/r) and jaundice (ATV), proximal renal tubulopathy and low bone mineral density (TDF), see Adverse Effects of ARVs and Drug Classes. 2. Prevention of long-term toxicity. Example of this proactive switch: prevention of lipoatrophy in persons receiving d4t or AZT and prevention of proximal renal tubulopathy with TDF, see Adverse Effects of ARVs and Drug Classes. 3. Avoid serious drug-drug interactions 4. Planned pregnancy 5. Ageing and/or co-morbidity with a possible negative impact of drug(s) in current regimen, e.g. on CVD risk, metabolic parameters. 6. Simplification: to reduce pill burden, adjust food restrictions and improve adherence. 7. Starting of HCV treatment in case of drug-drug interaction EACS Guidelines 9.0 October

30 Principles in switching: EACS guidelines 9.1» Clinicians should always review possible adverse events or tolerability issues with current antiretroviral regimens. Just because the HIV-VL is suppressed it should not be assumed that the HIV-positive person is well adapted and tolerating the current regimen. 1. The objectives of treatment modification should be to eliminate or improve adverse events, facilitate adequate treatment of co-morbid conditions, and improve quality of life. 2. The primary concern when switching should be to sustain and not to jeopardize virological suppression. In persons without prior virological failures and no archived resistance, switching regimens entail a low risk of subsequent failure if clinicians select one of the recommended combinations for first-line therapy. The majority of clinical trials showing non-inferiority of the new regimen after the switch have actively excluded persons with prior virological failures. 3. A complete ARV history with HIV-VL, tolerability issues and cumulative genotypic resistance history should be analysed prior to any drug switch. 4. A PI/r or PI/c may be switched to unboosted ATV, an NNRTI, or an INSTI only if full activity of the 2 NRTIs remaining in the regimen can be guaranteed. Switches have to be planned especially carefully when they result in a decrease in the genetic barrier of the regimen in case of prior virologic failures. Clinicians should review the complete ARV history and available resistance test and HIV-VL results before switching, and ensure no drug-drug interactions may lead to suboptimal drug levels (e.g. unboosted ATV and TDF).

31 Principles in switching: EACS guidelines Before switching, remaining treatment options in case of potential virological failure of the new regimen should be taken into consideration. For example, the development of the M184V RT mutation in HIV-positive persons who fail a 3TCcontaining regimen might preclude the future useof all currently available singletablet regimens. 6. Switches of single drugs with the same genetic barrier (for example EFV to RAL) is usually virologically safe in the absence of resistance to the new compound. 7. When selecting a new regimen, clinicians should carefully review the possibility of new drug-drug interactions with antiretroviral and concomitant medication, as well as the lag time for hepatic enzyme nduction or blockade following discontinuation of the offending drug. 8. If the switch implies discontinuing TDF and not starting TAF, clinicians should check the HBV status (avoid discontinuation of TDF in persons with chronic HBV and assess HBV vaccination status). 9. HIV-positive persons should be seen soon (e.g. 4 weeks) after treatment switches to check for maintenance of suppression and possible toxicity of the new regimen. 10. If a HIV-positive person receives and tolerates a regimen that is no longer a preferred option, there is no need to change. Example: persons tolerating EFVcontaining regimens.

32 Two Drug Regimens Pros and Cons Future Seite 32

33 Pts, Wk 96 (%) Long-Acting InSTIss Dual therapy with Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART: 96-Wk Results (LATTE-2)» Cabotegravir: InSTIs formulated as PO tablet and for long-acting IM injection» LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309) Injectable Rilpivirine requires cold chain IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) PO CAB + ABC/3TC (n = 56) Treatment Differences (95% CI) Q8W IM 10.0% 20 0 Virologic Success* Virologic Non-response No Virologic Data *HIV-1 RNA < 50 copies/ml. Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate / AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2% ~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB Q4W IM 3.0% Eron J, et al. IAS Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].

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