34
FIS 2013 Nov 11 th 2013 John Frater PROSPECTS FOR HIV CURE IN ADULTS
FIS 2013
Nov 11 th 2013
John Frater
PROSPECTS FOR
HIV CURE IN ADULTS
April 29th 2013;
Telegraph on-
line
What is ‘cure’?
Issues to consider:
Post treatment control – the benefit of
treating early
Anti-latency agents to activate the
reservoir
A role for immunotherapy
THE COMPONENTS OF A CURE….
The Problem: Barriers to an HIV Cure
HIV infects CD4+ cells. ‘Reservoir’ created
Reservoir size impacts clinical progression
Productively infected cell
Latently infected cell
Can we target ‘latent’ cells with new therapies
How do we measure the reservoir?
Can we identify those patients most amenable to cure?
?
?
?
What is ‘cure’?
Issues to consider:
Post treatment control – the benefit of
treating early
Anti-latency agents to activate the
reservoir
A role for immunotherapy
THE COMPONENTS OF A CURE….
Sterilising Cure vs
INFECTION MODEL
The ‘Berlin’ patient
Aviraemia – plasma
viral load <1 copy/ml
No replication
competent virus
No detectable HIV-
infected cells
‘Functional’ Cure
“CANCER” MODEL
Clinically
undetectable viraemia
in absence of ART
No disease
progression
No CD4 cell loss
No transmission
But…no agreed
duration
WHAT DO WE MEAN BY ‘CURING HIV’?
‘Sterilising’ cure– The Berlin Patient
What is ‘cure’?
Issues to consider:
Post treatment control – the benefit of
treating early
Anti-latency agents to activate the
reservoir
A role for immunotherapy
THE COMPONENTS OF A CURE….
Temps ?coul? depuis que l'ARN VIH -1 est ind ?celable (ann ?es)
AD
N V
IH-1
(L
og
co
pie
s/m
illi
on
de P
BM
C)
Temps ?coul? depuis que l'ARN VIH -1 est ind ?celable (ann ?es)
AD
N V
IH-1
(L
og
co
pie
s/m
illi
on
de P
BM
C)
Time on HAART (years)
Log
HIV
DN
A c
op
ies /
mill
ion
cells
Hocqueloux et al., AIDS 2010; 24:1598
Early ART impacts the reservoir
SPARTAC Trial
Chronic infection (n=135)
Acute infection(n=22)
The Original ‘Berlin Patient’ (NEJM, 1999)
Rosenberg (Nature 2000)
Hocqueloux et al (AIDS 2010)
Goujard et al (Antivir Ther 2012)
Lodi et al (Arch Intern Med 2012)
Saez-Cirion et al (Plos Path 2013 VISCONTI)
StÖhr et al (Plos One 2013; SPARTAC)
Evidence for ‘Post-treatment control’
French ANRS cohort study:
ART initiation within 10 weeks after acute
infection
ART for (at least) one year
Undetectable VL on treatment
VL remaining <400 cp/mL for (at least) 12
months after treatment interruption
VISCONTI
V IRO-IMMUNOLOGIC SUSTAINED CONTROL
AFTER TREATMENT INTERRUPTION
Code Sex Year of
diagnosis
PHI F iebig ART
in itiation
ART combination Time on
cART
(months)
Time since
interruption
(months)
CD4 T-cell counts
(cells/µL)
Last HIV-1
DNA (c/mL
106 PBMC)
HIV-1 RNA VL (c/mL
plasma)
HIV-1 RNA VL since
t reatment
interruption
First cART
discont.
Last At PHI
(Log)
Last during
follow-up
VL < 50 VL
50–400
VL
> 400
OR1 M 1996 Sympt V 2 NRTI 81 82 416 1057 959 134 4.3 <20 16/1
6
OR2 F 2001 Sympt V 3 NRTI+PI→3NRTI 24 101 955 906 743 6 6.8 2 24/2
6
2/26
OR3 F 1996 Sympt I 2 NRTI→2NRTI+PI 92 107 N/A 354 441 222 3.4 91 18/2
8
10/2
8
OR8 M 1998 Sympt III 2 NRTI+PI→3NRTI 60 72 502 915 886 122 5.0 <40 9/9
KPV M 2001 Sympt V NNRTI+2NRTI→3NR
TI
13 104 397 523 502 16 3.0 224 7/30 20/3
0
3/3
0
GXR F 1998 Sympt III 2 NRTI+PI 86 48 787 1636 1598 59 7.3 <40 5/5
CXK M 1999 Asymp V 2 NRTI+PI 39 75 593 976 787 38 4.3 289 9/12 3/12
MWP M 1999 Sympt V 2 NRTI+PI 12 115 371 1428 1400 120 7.1 1 21/2
1
JOGA F 2002 Sympt IV 2 NRTI+PI 17 72 393 734 779 8 5.9 <5 10/1
0
OCP M 2002 Sympt V 2 NRTI+PI→3NRTI 31 59 489 856 973 616 5.3 <20 11/1
1
LY1 M 2001 Sympt III 2 NRTI+PI→3NRTI 23 101 682 833 541 36 4.9 <20 23/2
3
LY2 M 2000 Asymp V 3 NRTI 56 84 455 938 492 44 4.4 <40 13/2
2
8/22 1/2
2
MO1 M 1999 Sympt V 2NRTI+PI→2NRTI+N
NRTI
48 93 580 1044 1251 13 6.0 5 13/1
3
SL2 M 1998 Sympt V 3 NRTI+PI→3NRTI 34 113 822 993 1299 140 3.1 5 13/1
4
1/14
MEDIAN 1999 V 36.5 89 502 927 837 51.5 5.0 <20
VISCONTI: DURATION OF ART AT
PRIMARY HIV INFECTION MATTERS
Saez-Cirión A, et al. PLoS Pathog 2013;9:e1003211.
Time on
cART
(months)
Time since
interruption
(months)
81 82
24 101
92 107
60 72
13 104
86 48
39 75
12 115
17 72
31 59
23 101
56 84
48 93
34 113
36.5 89
3538 patients <6 months of PHI 756 patients treated within 6 months and at least for a year 74 patients with VL<50 RNA copies/ml who stop (ie only 2% of PHI patients
Probability of control at 24 months : 15.7% [6.5-28.5]
Months post-treatment interruption
Pro
po
rtio
n w
ith
de
tect
able
vir
aem
ia
Saez-Cirion et al PLoS Path 2013
French Hospitals Database on HIV Treatment in PHI and frequency of PHI
Objective: to determine the ef fect of shor t course ART compared with no ART in p r imary H IV in fection (PHI)
PHI: <6 months since estimated date of seroconversion
N=371; Randomised to 3 arms
48-weeks ART (ART-48)
12-weeks ART (ART-12)
No therapy (Standard of Care, SOC)
Primary endpoint
Time to CD4 < 350 cells/mm3 or long-term ART initiation
THE SPARTAC TRIAL – EVIDENCE FOR PTC?
Fidler S, et al. N Engl J Med 2013;368:207–17.
THE SPARTAC TRIAL; HIV RNA REBOUND
FOLLOWING ART INTERRUPTION C
ha
ng
e i
n l
og
10
HIV
RN
A f
rom
ba
se
lin
e
Weeks from ART interruption or randomisation (SOC)
.8
.6
.4
.2
0
2 3 4 6 12 24 36 48 60
ART-48
ART-12
SOC
Fidler et al, NEJM, 2013
Patient demographics n = 165
Sex, n (%)
Male 110 (67)
Female 55 (33)
Age, median (IQR) 34 (27–41)
Risk, n
MSM 101
Heterosexual 62
Not Known 2
Estimated time since
seroconversion, days (IQR)
85 (60–101)
CD4 cell count, cells/µL
(IQR)
565 (463–707)
Plasma HIV-1 VL, RNA c/mL
(IQR)
24,293 (4540–108,928)
Median follow-up, weeks
(IQR)
167 (108–199)
SPARTAC: SUB-ANALYSIS
Of the 165 participants:
• 161 had viral rebound (> 400
RNA c/mL)*
– The majority had VL
rebound within 12 weeks of
stopping ART
– Four participants
maintained VL < 400 c/mL
for 164–202 weeks
• Are they PTCs?
*On two separate occasions. Two had only one
VL≥ 400 c/ml followed by initiation of long-
term ART or loss to follow-up
Stöhr W, et al. PLoS ONE 2013;8(10): e78287
IMPACT OF ART DURATION:<12 VS >12 WEEKS
0.00
0.20
0.40
0.60
0.80
1.00
Pro
babi
lity
of n
ot h
avin
g V
L r
ebo
und
79 27 20 16 13 11 6 5 5 4 3 3 3 3 2 2 2 0ART = >12 weeks
86 18 11 9 7 3 3 3 3 3 2 2 2 2 1 0 0 0ART = <=12 weeks
Number at risk
0 12 24 36 48 60 72 84 96 108
120
132
144
156
168
180
192
204
Weeks from ART stop
ART = <=12 weeks ART = >12 weeks
Time to confirmed VL >=400
12 weeks 52 weeks 104 weeks
ART >12 weeks 32% 14% 5%
ART <12 weeks 21% 4% 4%
Probabilities of remaining undetectable (<400 copies/ml)
P=0.06; log-rank
test
Pro
po
rtio
n w
ith
un
de
tecta
ble
vir
ae
mia
Ho et al, Cell 2013; 155, 540-551
MUTATED VIRAL GENOMES DOMINATE
THE RESERVOIR
What is ‘cure’?
Issues to consider:
Post treatment control – the benefit of
treating early
Anti-latency agents to activate the
reservoir
A role for immunotherapy
THE COMPONENTS OF A CURE….
PMA – Protein Kinase C agonist
TNFa – MAPK / NFkB signall ing Methylation inhibitors
5-aza-2’-deoxycytidine (5-aza-dC)
Prostratin – Protein Kinase C agonist
Histone Deacetylase Inhibitors (HDACi )
Sodium valproate
Disulfiram
Vorinostat (Class 1 and 2 inhibitor 1,2,3,4,5,6,7,8,9,10)
Panobinostat (Pan HDACi)
Romidepsin (Class 1 and 2)
‘ANTI-LATENCY AGENTS’
HDACI ACTIVITY - U1 CELL LINE
HDAC INHIBITORS – EASY
HDAC INHIBITORS – COMPLEX
Unpublished: Slide courtesy of Sharon Lewin
What is ‘cure’?
Issues to consider:
Post treatment control – the benefit of
treating early
Anti-latency agents to activate the
reservoir
A role for immunotherapy
THE COMPONENTS OF A CURE….
DO LATENT CELLS PRODUCE ANTIGEN?
Pace et a l , 2013 Plos Pathogens 8(7) : e1002818
Vorinostat does not reliably lead to CD8 T cell induced cell
killing
Shan et al. Immunity 2012
What is the interaction between the new ‘anti-
latency drugs’ and the immune response?
UK-based trial:
recruiting 2014
Managed by CHERUB
3 interventions:
Early ART
Vaccination
HDACi
Primary Outcome:
Change in Reservoir Size
THE SOLUTION?:
PHI + HDACi + VACCINE
CHERUB Collaborative HIV Eradication of
Reservoirs: UK Biomedical Research Centres
WEBSITE: WWW.CHERUB.UK.NET
and Twitter!!…….@ukcherub
Acknowledgements Peter Medawar Building, Oxford
• James Williams
• Matt Pace
• Helen Brown
• Matt Jones
• Jacob Hurst
• Nicola Robinson
• Rodney Phillips
The Kirby Institute, UNSW
• Tony Kelleher
• Kersten Koelsch
Imperial College, London
• Jonathan Weber
• Sarah Fidler
UPenn
• Una O’Doherty
Medical Research Council, Clinical Trials unit
• Wolfgang Stöhr
• Abdel Babiker
• Kholoud Porter
Participants of SPARTAC
• The SPARTAC trial Investigators
www.cherub.uk.net Twitter: @ukcherub
