CROI 2018: Top Ten forClinicians

Josep M LlibreHospital Universitari Germans Trias i Pujol

Fundació “Lluita contra la SIDA”Badalona, Barcelonajmllibre@flsida.org

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: % <50 c/mL (Snapshot) Primary endpoint at Week 48: % <50 c/mL

(Snapshot)

DTG (50 mg BID) + 2 NRTIs (n = 69)

EFV (600 mg QD) + 2 NRTIs (n = 44)

TB therapy

HIV/TB coinfectedART-naive adults

Inclusion criteria• HIV-1 RNA ≥1000 copies/mL and CD4+ ≥50 cells/mm3

• Pulmonary, pleural, or lymph node tuberculosis with RIF-sensitive MTB confirmed by culture or GeneXpert

• RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date

DTG:EFV 3:2 randomization stratified by• Screening plasma HIV-1 RNA ≤100,000 or >100,000 copies/mL• Screening CD4+ ≤100 cells/mm3 or >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 <50 copies/mL, % (95% CI)

DTG (n=69)

EFV (n=44)

81 (72, 90)

89 (79, 98)

Modified FDA snapshot analysis (ITT-E) Pre-dose concentration: DTG 50 mg BID with RIF

Time n DTG Conc (ng/mL)Geomean (90%CI) %CV

Wk 8 41 852 (208-2340) 118

Wk 24 22 942 (19-3380) 276

Pre-dose concentration: DTG 50 mg QD without RIF (post-TB treatment phase)

Time n DTG Conc (ng/mL)Geomean (90%CI) %CV

Wk 36 16 1143 (80-4370) 151

Wk 48 12 591 (19-3310) 359

INSPIRING Pharmacokinetic Data

INSPIRING DTG Ctau when administered BID with RIF similar to DTG 50 mg QD without RIF and to previously reported data for DTG 50 mg QD in Phase 2/3 HIV trials.

• 5 D/C (DTG) lost to F/U or consent withdrawal. No emergent resistance. No dif in AEs. IRIS: 20%.

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

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<100 cells/µl

• Follow-up to week 48– Safety bloods at screening, weeks 4 and 48; FBC & CD4 at weeks 0, 12, 24, 36, 48; Viral loads retrospectively at

weeks 0, 4, 12, 24, 48

• Primary endpoint: 24-week mortality

• Two other factorial randomisations investigated

– 12 weeks enhanced prophylaxis (Hakim et al., NEJM 2017)

– 12 weeks supplementary food (Mallewa et al.CROI 2017; Lancet HIV, in press)

•11

Initiate ART with 2NRTI+NNRTI alone (standard of care)

Initiate ART with 2NRTI+NNRTI+12 weeks

additional raltegravir

1:1 randomisation

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

VL<50 copies/ml

•12

p<0.0001 p<0.0001 p=0.36 p=0.47

Raltegravir-intensified

Standard

Overall p<0.0001

13.4%

51.7%

74.7%79.2%

41.0%

71.9%76.7%

80.7%

0

20

40

60

80

100

Per

cent

age

with

VL<

50 c

opie

s/m

l (95

% C

I)

0 4 12 24 48Week since randomisation (ART initiation)

• Median CD4 37 cells; VL>105: 74%.

• VL decay at week 4: RAL -3.4 log, No RAL -2.7 log (p<0.001)

• No dif in mortality, VL<50 at week 48,

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

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<0.01), TBC (p=0.01), younger age (p=0.03), enhanced prophylaxis (p=0.01). NOT associated with VL.

RAL did not protects against NRTI/NNRTI Resistance (#531).

050

100

150

Ev e

n tra

te/1

00PY

(ha z

a rd )

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

Standard Raltegravir-intensified

Our data provide reassurance that the current move to first-line INSTI-based ART will not increase IRIS:

• Similar rapid VL reductions with all integrase inhibitors• Results can likely be extrapolated to other INSTIs, including dolutegravir

•ANRS: INSTIs NOT associated with IRIS (#495). Cohorts vs RCT.

� High n (1805)

� CD4 < 100; High VL

� Countries with high incidence of TBC and OIs

� INSTI vs non-INSTI, randomized

� Blinded data analysis

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 <250 cells

• Stratified by CD4 count and ART naive (50%) (only EFV or NVP allowed).

• 1 m: Daily Rifapentine 450 mg (<45 kg) or 600 mg (>45 kg) + INH 300 mg/d; 9 m INH 300 mg/d.

No differences in:

• Active TBC (confirmed)

• Active TBC (probable)

• Death related to TBC

• Any death

• Drug-resistanct TBC

• G≥3 AEs: 1HP more hematologic, 9H more

hepatic or neurologic.

More targeted safety events (liver, HSR…)

with 9 INH (p=0.016)

All outcomes incidence per 100 PY: 0.67 (9m) vs 0.65 (1m); 95% CI -0.30-0.35.

Predefined noninf margin: 1.25 per 100 PY

Time to endpoint: TB or death

R Chaisson. CROI 2018. Boston, MA. #37LB.

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<0.0001)

Adoptive Transfer of 30x10 6 LNMC+PBMC From AviremicMonkeys (Day 140) into Naïve Recipients

Time to Viral Rebound Following ART Discontinuation

• Residual PGT121 cannot explain the delay in rebound; levels <1 mg/ml

(rebound threshold) for >2 months prior to ART withdrawal

• Mechanism may involve activation of infected CD4+ T cells by GS-9620

followed by enhanced binding and clearance by PGT121; no evidence of a

bNAb induced “vaccinal effect”

� These data suggest that bNAbs combined with an innate immune

stimulant may effectively target the viral reservoir

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

Boston Logan Intl Airport. •Courtesy of Benjamin Young