PROSPECTS FOR HIV CURE IN ADULTS FIS 2013 Nov 11 th 2013 John Frater
April 29 th 2013; Telegraph online
THE COMPONENTS OF A 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 Problem: Barriers to an HIV Cure HIV infects CD4+ cells. Reservoir created? Can we target latent cells with new therapies Reservoir size impacts clinical progression Latently infected cell Productively infected cell? How do we measure the reservoir?? Can we identify those patients most amenable to cure?
THE COMPONENTS OF A 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
WHAT DO WE MEAN BY CURING HIV? Sterilising Cure vs Functional Cure INFECTION MODEL The Berlin patient Aviraemia plasma viral load <1 copy/ml No replication competent virus No detectable HIVinfected cells CANCER MODEL Clinically undetectable viraemia in absence of ART No disease progression No CD4 cell loss No transmission But no agreed duration
Sterilising cure The Berlin Patient
THE COMPONENTS OF A 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
Log HIV DNA copies / million cells ADN VIH -1 (Log copies/million de PBMC) Early ART impacts the reservoir Hocqueloux et al., AIDS 2010; 24:1598 SPARTAC Trial Chronic infection (n=135) Acute infection(n=22) Time on HAART (years) Temps?coul? depuis que l'arn VIH -1 est ind?celable (ann?es)
Evidence for Post-treatment control 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)
VISCONTI VIRO-IMMUNOLOGIC SUSTAINED CONTROL AFTER TREATMENT INTERRUPTION 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
Code Sex Year of diagnosis VISCONTI: DURATION OF ART AT PRIMARY HIV INFECTION MATTERS PHI F iebig ART initiation ART combination Time on cart (months) Time since interruption (months) CD4 T-cell counts (cells/µl) First cart discont. Last Last HIV-1 DNA (c/ml 106 PBMC) HIV-1 RNA VL (c/ml plasma) At PHI (Log) Last during follow-up 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 OR3 F 1996 Sympt I 2 NRTI 2NRTI+PI 92 107 N/A 354 441 222 3.4 91 18/2 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 HIV-1 RNA VL since t reatment interruption VL < 50 VL 50 400 13 104 397 523 502 16 3.0 224 7/30 20/3 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 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 MEDIAN 1999 V 36.5 89 502 927 837 51.5 5.0 <20 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 2/26 10/2 8 VL > 400 3/3 0 8/22 1/2 2 1/14
Proportion with detectable viraemia French Hospitals Database on HIV Treatment in PHI and frequency of PHI 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 Saez-Cirion et al PLoS Path 2013
THE SPARTAC TRIAL EVIDENCE FOR PTC? Objective: to determine the ef fect of short course ART compared with no ART in primary HIV infection (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/mm 3 or long-term ART initiation Fidler S, et al. N Engl J Med 2013;368:207 17.
Change in log10 HIV RNA from baseline THE SPARTAC TRIAL; HIV RNA REBOUND FOLLOWING ART INTERRUPTION 0.2.4.6 SOC ART-12 ART-48.8 12 24 36 48 60 Weeks from ART interruption or randomisation (SOC) Fidler et al, NEJM, 2013
SPARTAC: SUB-ANALYSIS 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) CD4 cell count, cells/µl (IQR) Plasma HIV-1 VL, RNA c/ml (IQR) Median follow-up, weeks (IQR) 85 (60 101) 565 (463 707) 24,293 (4540 108,928) 167 (108 199) 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 longterm ART or loss to follow-up Stöhr W, et al. PLoS ONE 2013;8(10): e78287
IMPACT OF ART DURATION:<12 VS >12 WEEKS Proportion with undetectable viraemia Probabilities of remaining undetectable (<400 copies/ml) 1.00 0.80 0.60 Time to confirmed VL >=400 P=0.06; log-rank test 0.40 0.20 0.00 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 Number at risk ART = <=12 weeks ART = >12 weeks Weeks from ART stop 86 18 11 9 7 3 3 3 3 3 2 2 2 2 1 0 0 0 79 27 20 16 13 11 6 5 5 4 3 3 3 3 2 2 2 0 ART = <=12 weeks ART = >12 weeks 12 weeks 52 weeks 104 weeks ART >12 weeks 32% 14% 5% ART <12 weeks 21% 4% 4%
MUTATED VIRAL GENOMES DOMINATE THE RESERVOIR Ho et al, Cell 2013; 155, 540-551
THE COMPONENTS OF A 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
ANTI-LATENCY AGENTS PMA Protein Kinase C agonist TNFa MAPK / NFkB signalling 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)
HDACI ACTIVITY - U1 CELL LINE
HDAC INHIBITORS EASY
HDAC INHIBITORS COMPLEX
Unpublished: Slide courtesy of Sharon Lewin
THE COMPONENTS OF A 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
DO LATENT CELLS PRODUCE ANTIGEN? Pace et al, 2013 Plos Pathogens 8(7): e1002818
What is the interaction between the new antilatency drugs and the immune response? Vorinostat does not reliably lead to CD8 T cell induced cell killing Shan et al. Immunity 2012
THE SOLUTION?: PHI + HDACi + VACCINE UK-based trial: recruiting 2014 Managed by CHERUB 3 interventions: Early ART Vaccination HDACi Primary Outcome: Change in Reservoir Size
CHERUB Collaborative HIV Eradication of Reservoirs: UK Biomedical Research Centres
WEBSITE: WWW.CHERUB.UK.NET and Twitter!!.@ukcherub
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 Acknowledgements Medical Research Council, Clinical Trials unit Wolfgang Stöhr Abdel Babiker Kholoud Porter www.cherub.uk.net Twitter: @ukcherub Participants of SPARTAC The SPARTAC trial Investigators