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Transcript of CROI 2018: Top Ten for Clinicians · CROI 2018: Top Ten for Clinicians Josep M Llibre Hospital...

  • CROI 2018: Top Ten forClinicians

    Josep M LlibreHospital Universitari Germans Trias i Pujol

    Fundació “Lluita contra la SIDA”Badalona, [email protected]

    Boston, MA, US. March 4-7, 2018

  • 1. ANDES, naives: gen DRV/r/3TC non-inf to gen DRV/r + TDF/3TC.

    2. GS 1844, switch: DTG/ABC/3TC to BIC/F/TAF non-inf.

    3. INSPIRING: DTG BID OK in TBC (with RIF).

    4. REALITY: RAL not associated with fatal or non-fatal IRIS.

    5. A5279/BRIEF TB: Ultra-short TB prevention 1 month RIP/INH in HIV+, non-inf.

    6. ACTG 5288 “Strategy” ART: it’s time to rethink 3RD line ART in 3RD world.

    7. SWISS HCVree: Elimination of HCV in HIV+ MSM.

    8. Hair PK ARV levels feasible, easy, strongest predictor of VF (A5257).

    9. A Tri-specific bNAb offers complete protection in macaques.

    10. PGT121 + GS-9620 Delays Viral Rebound in SHIV-Infected Monkeys (…CURE?)

  • • N=145, naives. Open-label.

    • No entry restrictions (HBsAg -).

    • Stratified by VL (≤ or >105 c/mL)

    • Median CD4 383 cells; % VL>105: 24%.

    • Similar CD4 recovery.

    • 1 VF (TT), no R.

    • No dif AEs; D/C AEs “rare” and similar.

    TT vs DT: 94 vs 93% ; -1.0:-7.5, 5.6)

    (VL > 105: 92 vs 91%)PP (n=140): 99 vs 100%

    ANDES: gen DRV/r/3TC non-inf to gen DRV/r + TDF/3TC.

    P Cahn. CROI 2018, Boston, MA. #489.

  • JM Molina. CROI 2018, Boston, MA. #22.

  • • No treatment-emergent resistance.

    • 2 deaths (B/c/F/TAF): male, 71 y.o., sudden death, atherosclerotic CVD on autopsy.

    • D/C AEs: 2% vs 1%. Study drug-related AEs: 8% vs 16% (p=0.01).

    • No dif. kidney tubular markes, bone DEXA, or lipids (except TG, better BIC). JM Molina. CROI 2018, Boston, MA. #22.

  • Switch EVG/c/F/TFV (or ATV/r) to B/F/TAF in women: non-inf.

    C Kityo. CROI 2018. Boston, MA. #500.

    • No treatment emergent resistance B/C/F/TAF. No differences found between arms.

  • Double-blind triple-arm RCT:which coffee is worse?

    1

    2

    Hynes Convention Center. CROI 2018, Boston, MA.

  • Conference on Retroviruses and Opportunistic Infect ions; March 4-7, 2018; Boston, MA

    INSPIRING: Phase IIIb Study Design

    Dooley et al. CROI 2018; Boston, MA.

    Phase IIIb, randomized, multicenter, open-label, act ive-control parallel-group study

    HR (4 months) a

    Day 1 52 weeksEnd of randomized phase

    24 weeks

    DTG (50 mg QD) + 2 NRTIs

    Interim analysis: % 100 cells/mm3

    DTG dose switch2 weeks post-completion of TB treatment

    Screening−28 to −14 days

    HRZE (2 months)

    • Median CD4: 206 cells, 60% VL>105, 40% female.

    KE Dooley. CROI 2018. Boston, MA. #33.

  • Conference on Retroviruses and Opportunistic Infect ions; March 4-7, 2018; Boston, MA

    Virologic and Immunologic Results in the ITT -E Population Through Week 24

    Dooley et al. CROI 2018; Boston, MA.

    -20

    0

    20

    40

    60

    80

    100

    -4 0 4 8 12 16 20 24 28

    Per

    cent

    age,

    %

    Week

    Proportion of Participants With HIV-1 RNA

  • BIC (either BID) cannot be administered with RIF

    Daily BIC exposure (AUC0‒24) expected to be ~60% lower with B/F/TAF bid + RIF vs B/F/TAF QD

    JM Custodio. CROI 2018. Boston, MA. #34.

  • REALITY: Trial Design

    • 1805 ART-naïve HIV-infected adults, adolescents & children

    ≥5 years with CD4

  • VL

  • Incidence of fatalIRIS-compatible events

    •13

    36 (4.0%) RAL vs 31 (3.4%) standard experienced fatal IRIS (p=0.54),

    occurring a median 4.4 (IQR 2.6-9.4) weeks after ART initiation

    010

    2030

    4050

    Dea

    thra

    te/1

    00P

    Y(h

    a za r

    d )

    0 8 16 24 32 40 48Week since randomisation (ART initiation)

    Standard Raltegravir-intensified

    D Gibb. CROI 2018. Boston, MA. #23.

  • D Gibb. CROI 2018. Boston, MA. #23.

    Incidence of fatal and non-fatal IRIS-compatible events

    •14

    Fatal/non-fatal IRIS-compatible events: 89 (9.9%) RAL-intensified vs 86 (9.5%) standard (p=0.79).

    No dif in Fatal IRIS (n=67 events).

    IRIS associated with: lower CD4 (p

  • A5279/BRIEF TB: Ultra-short TB prevention 1 month RIP/INH in HIV+.

    • N=3000 HIV+ with: TST+ (32%), IGRA+ (4%), or living in an endemic area. 13% CD4

  • Boston Common Park. Courtesy of Hortensia Alvarez.

  • Cohort A

    No LPV/r resistance; Susceptible to ≥1 NRTI

    Continue 2 nd line ART

    Cohort C

    Resistant to LPV/r & ETR; Susceptible to DRV/r; no

    prior RAL

    Best available NRTIs, DRV/r & RAL

    Cohort D

    Not eligible for Cohorts A, B, or C

    Best available local & study supplied ARVs

    Cohort B1Best available NRTIs, RAL &

    DRV/r

    Cohort B2ETR, RAL &

    DRV/r

    Cohort allocation based on ARV History and Genotype (n=545)

    Cohort B3RAL, DRV/r &

    TDF/FTC

    Cohort B

    Resistant to LPV/r; Susceptible to DRV/r &

    ETR;no prior RAL

    Randomized 1:1

    HBV +

    3rd line, salvage (VL>1000)

    • >24 weeks on 2nd line PI

    • 57% ≥2 class resistance; 9 y on ART

    • South Africa, Brazil, India

    • CD4 175 cells, VL>105: 31%.

    A5288

    B Grinsztejn. CROI 2018. Boston, MA. #30LB

    97% susceptible to DRV

  • Baseline Resistance by Drug Class and Cohort

    C(N=70)

    D(N=34)

    Total(N=545)

    B(N=154)

    A(N=287)

    PI0

    20

    40

    60

    80

    100

    NNRTINRTI

    Pe

    rce

    nt

    (%)

    56% M184V 78% ETR susceptible

    LPV S 63%DRV S 97%

    B Grinsztejn. CROI 2018. Boston, MA. #30LB

  • Primary Outcome:

    HIV-1 RNA ≤ 200 copies/mL at 48 weeks

    44% 88% 88% 100% 90% 74% 64%

    A(N=287)

    B1(N=74)

    B2(N=72)

    B3(N=8)

    C(N=70)

    D(N=34)

    Total(N=545)

    Pe

    rce

    nt

    (%)

    0

    20

    40

    60

    80

    100

    B Grinsztejn. CROI 2018. Boston, MA. #30LB

  • Primary Outcome:

    HIV-1 RNA ≤ 200 copies/mL at 48 weeks

    44% 88% 88% 100% 90% 74% 64%

    A(N=287)

    B1(N=74)

    B2(N=72)

    B3(N=8)

    C(N=70)

    D(N=34)

    Total(N=545)

    Pe

    rce

    nt

    (%)

    0

    20

    40

    60

    80

    100

    B Grinsztejn. CROI 2018. Boston, MA. #30LB

  • Primary Outcome:

    HIV-1 RNA ≤ 200 copies/mL at 48 weeks

    44% 88% 88% 100% 90% 74% 64%

    A(N=287)

    B1(N=74)

    B2(N=72)

    B3(N=8)

    C(N=70)

    D(N=34)

    Total(N=545)

    Pe

    rce

    nt

    (%)

    0

    20

    40

    60

    80

    100

    B Grinsztejn. CROI 2018. Boston, MA. #30LB

  • B Grinsztejn. CROI 2018. Boston, MA. #30LB

    2o Outcome: Cumulative Incidence of Confirmed VF

    A

    Total

    D

    Cohort % VF% VF with

    new mutation(s)

    A 51% 17%B1 8% 1%B2 6% 3%B3 0% 0%C 7% 1%D 18% 15%

    Total 30% 10%

    NAMIBIA, n=238 VF 2ND line (CDC, PEPFAR)

    MR Jordan. #541.

    � DRV/r and RAL +/- ETR regimens were highly effective for participants with LPV/r resistance who presented for 3rd line ART.

    � More than ½ of participants without LPV/r resistance who remained on 2nd line ART did not achieve sustained virol suppression at week 48.

  • Swiss HCVree

    Identify HCV spreadersHCV RNA every 6 months

    DL Braun. CROI 2018.Boston, MA: #81LB.

  • DL Braun. CROI 2018.Boston, MA: #81LB.

  • • �49% incident HCV (TasP)

    • �92.5% prevalent HCV

    DL Braun. CROI 2018.Boston, MA: #81LB.

  • Intl vs Domestic HCV transmission?Locating Swiss sequences in transmission clusters

    * Incident Swiss HCV infections

    in HIV+ MSM

    * Outside Switzerland

    * Unknown

    * Chronic from Switzerland

    • 90% of sequences from acute

    infections in Swiss MSM are within

    transmission clusters.

    • 14% to 44% of sequenced infections

    were likely acquired by contacts with

    MSM not living in Switzerland

    (Germany, Netherlands, UK).

  • Hair has some advantages over other PK measures

    • Plasma levels measure short-term adherence• DBS levels good for ARVs requiring intracellular

    phosphorylation (e.g. TFV/FTC)

    • Occiput hair grows steadily at ~1cm/month so becomes marker of time (segmental analysis)

    • Hair easy and cheap to collect, store and ship at room temp without biohazard

    • UCSF Hair Analytical Lab has developed assays for analyzing multiple ARVs in hair

    Gandhi M Ann Intern Med 2002; Huang Y. RCM 2008; Phung N. RCM 2018; Difrancesco R. TDM 2013 Beumer JH. Int J Clin Prac 2001; Gandhi M. Ann Intern Med 2002; Hickey M. JAIDS 2014; Thaden J. CROI 2018 M Gandhi. CROI 2018. Boston, MA. #24.

  • • Hair samples collected at weeks 4, 8, 16, and then quarterly.

    • Hair & VL data available for 2192 person-visits among 599 pts.

    • VF 96 weeks: 26%, 6%, and 3% for lowest, middle and highest tertiles.

    • HR VF 6.8 lowest vs highest tertile.

    • Similar results for males and females.

    • Weak correlation with self-reported adherence.

    • Strongest predictor of VF, first RCT.

    Pro

    po

    rtio

    n w

    ith

    ou

    t vi

    rolo

    gic

    failu

    re

    Weeks

    Time to virologic failure by tertile of hair concentration

    706 person-visits for ATV arm; 776 person-visits for DRV; 710 person-visits for RAL.

    Curves estimated for hypothetical persons remaining in the given tertile throughout

    follow-up. Tertiles of the actual participants could change over time

    HR 1.71 (0.52-6.53, p 0.39)

    HR 1.00

    The hazard of virologic

    failure with hair levels in

    the lowest tertile is almost

    7X that with levels in the

    highest tertile

    HR 6.79 (2.65-23.00, p 0.004)

    ACTG 5257. Hair subanalysis.

    26 52 78 104

    M Gandhi. CROI 2018. Boston, MA. #24.

  • Mono-specific snack

    Tri-specific snack

  • New trispecific Ab format from Sanofi

    Amenable for Long Acting formulation similar to parental bnAbs

    IgG3 “open”

    A Pegu. CROI 2018. Boston, US. #113LB.

  • Broadly Neutralizing Antibodies Against HIV-1

    0.010.11100

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    Potency (IC 80 at µg/ml)

    Bre

    adth

    VRC01

    N610E8v4

    CAP256.VRC26.25

    PGDM1400

    PGT121

    2F5

    2G12 35022

    3BNC117

    4E10

    VRC34.01

    10-1074

    b12

    PG9

    PGT151

    PGT145

    VRC07-523

    50

    A Pegu. CROI 2018. Boston, US. #113LB.

  • Trispecific and bnAb sensitivity of SHIVs

    Antibody SHIV BaLP4 SHIV 325C

    VRC01 0.067 >50

    PGDM1400 >50 0.015

    10E8 0.475 12.8

    VRC01/PGDM1400-

    10E8v40.055 0.168

    IC50 (µg/mL)

    Combination of SHIV BaL and SHIV325c was selected for in vivo challenge study

    Inject Ab

    Dual SHIV IR

    challenge

    0 5 7 14 21 8 35 42 49

    Days

    Samples collected until Day 96

    5 mg/kg IV

    N=24 macaques challenged intrarectally with both SHIV viruses simultaneously.

    A Pegu. CROI 2018. Boston, US. #113LB.

  • 0 5 10 15 20 25 30 35 40 45 50101

    102

    103

    104

    105

    106

    107

    VRC01

    Days post SHIV challenge

    Pla

    sma

    Vira

    l Loa

    d (c

    opie

    s/m

    l)A12V123

    A13X029

    A12V099

    A13X032

    A14V135

    A14V098

    A14V154

    A13X048

    0 5 10 15 20 25 30 35 40 45 50101

    102

    103

    104

    105

    106

    107

    108

    PGDM1400

    Days post SHIV challenge

    Pla

    sma

    Vira

    l Loa

    d (c

    opie

    s/m

    l)

    A13V133

    A13V018

    A14V169

    A13X026

    A14V085

    A14V040

    A14V091

    A13X037

    0 5 10 15 20 25 30 35 40 45 50101

    102

    103

    104

    105

    106

    107

    VRC01/PGDM1400-10E8v4

    Days post SHIV challenge

    Pla

    sma

    Vira

    l Loa

    d (c

    opie

    s/m

    l)

    A13V114

    A13V070

    A12V068

    A13V105

    A14V058

    A14V170

    A14V086

    A13X046

    Plasma Viremia

    AntibodyNo. of

    animals

    No. of

    animals

    infected

    VRC01 8 6

    PGDM1400 8 5

    VRC01/PGDM1400-10E8v4 8 0

    *Fisher exact test, p= 0.0058

    Trispecific antibody provided complete protection compared to partial protection by the single bnAbs

    N=8 (6/8)N=8 (5/8)

    N=8 (0/8)

    A Pegu. CROI 2018. Boston, US. #113LB.

  • CROI Auditorium. Hynes Convention Center, Boston, MA.

  • PGT121 (bNAb) Combined with GS-9620 (TLR7 agonist) Delays Viral Rebound in SHIV-Infected Rhesus Monkeys

    Aim: To assess anti-reservoir activity of bNAbs (beyond ARV activity)

    • 44 rhesus monkeys infected IR with SHIV-SF162P3. ART (TDF/FTC/DTG) initiated at week 1 (day 7)

    • Prolonged ART suppression x 96 weeks.

    • TLR7 agonist: 10 x GS-9620 by oral gavage at weeks 96, 98, 100, 102, 104, 106, 108, 110, 112, 114

    • PGT121: 5 x PGT121 infusions at weeks 106, 108, 110, 112, 114

    • ART discontinued at week 130 (16 weeks after last PGT121/TLR7)

    Dan H Barouch. CROI 2018. Boston, MA. #73LB

  • Broadly Neutralizing Antibodies Against HIV-1

    0.010.11100

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    Potency (IC 80 at µg/ml)

    Bre

    adth

    VRC01

    N610E8v4

    CAP256.VRC26.25

    PGDM1400

    PGT121

    2F5

    2G12 35022

    3BNC117

    4E10

    VRC34.01

    10-1074

    b12

    PG9

    PGT151

    PGT145

    VRC07-523

    50

    A Pegu. CROI 2018. Boston, US. #113LB.

  • No PGT121 PK levels in Lymph Nodes and Colorectal B iopsies for 10 Weeks Before ART Discontinuation (Week 120)

    PGT121+TLR7PGT121

    PG

    T12

    1 ( µ

    g/m

    l)CR-L CR-S LN-L LN-S Ctrl-L Ctrl-S

    0

    100

    200

    300

    PGT1

    21 ( µ

    g/m

    l)

    CR-L CR-S LN-L LN-S0

    100

    200

    300CR colorectal tissue

    LN lymph node

    L cell lysate

    S supernatant

    Ctrl positive control

    • No PGT121 plasmal LN or colorectal biopsies levels for 8-10 Weeks before ART D/C

    • No/Minimal SHIV-Specific CD8 T Cell Responses in PBMC or Lymph Nodes

    • GS-9620 Administration Activates CD4 T Cells

    • PGT121 + GS-9620 Reduces Viral DNA in PBMCs and Lymph Nodes to undetectable

  • SHIV RNA Following ART Discontinuation

    Days Following ART Discontinuation

    Log

    SH

    IV R

    NA

    Cop

    ies

    / ml

    Sham TLR7

    PGT121+TLR7PGT121

    11/11 Rebound (100%) 10/11 Rebound (91%)

    9/11 Rebound (82%) 6/11 Rebound (55%)

    Dan H Barouch. CROI 2018. Boston, MA. #73LB

  • PGT121 + GS-9620 Delays Time to Viral Rebound Follo wing ART Discontinuation

    P = 0.001

    PGT121 + GS-9620 (and PGT121):

    • Delays Time to Viral Rebound Following ART D/C (p=0.0006)

    • Reduces Peak and Setpoint Viral Loads Following ART D/C (p

  • Boston Logan Intl Airport. •Courtesy of Benjamin Young