The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
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The State of the Art in HIV Cure Research – Hope or Hype: What Does It Mean for Patients
Joseph Eron, M.D., of University of North Carolina at Chapel Hill, presents "The State of the Art in HIV Cure Research – Hope or Hype: What Does It Mean for Patients" at AIDS Clinical Rounds
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The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
The State of the Art in HIV Cure
Research— Hope or Hype
Joseph J. Eron, Jr., MD Professor of Medicine
The University of North Carolina
Disclosures
• Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from Argos, Bristol-Myers Squibb, GlaxoSmithKline/ViiV, Gilead Sciences, Janssen, Kainos, Koronis, Merck, and Tobira; has served on the data and safety monitoring board for Vertex; and has served as a principal investigator for research with funds paid to the University of North Carolina from Bristol-Myers Squibb, GlaxoSmithKline/ViiV, and Tobira.
What percentage of your patients have asked whether
HIV can be cured?
1. < 5% 2. 5%-25% 3. 25%-75% 4. Almost everyone has asked at one time
or another
Why Cure HIV? • Shortened life expectancy of HIV-infected
persons, even with treated HIV infection[1]
• Cost, consequences (known and unknown) and the impact on QOL of antiretroviral therapy[2]
– ART needed for decades of life with high level of adherence[2]
• Stigma, discrimination, fear of transmission, isolation[3]
• Global burden of HIV-1 disease[4]
1. Lohse N, et al. Ann Intern Med. 2007;146:87-95. 2. Volberding PA, et al. Lancet. 2010;376:49-62. 3. Parker R, et al. Soc Sci Med. 2003;57:13-24. 4. Mathers CD, et al. PLoS Med. 2006;3:e442.
HIV-1 CAN BE CURED
The State of the Art in HIV Cure Research— Hope or Hype
CAN HIV-1 BE CURED? Berlin Patient
Hütter G, et al. N Engl J Med. 2009;360:692-698.
Substantial graft vs host disease
1. Hütter G, et al. N Engl J Med. 2009;360:692-698. 2. Allers K, et al. Blood. 2011;117:2791-2799.
Yukl et al PLoS Pathogens May 2013
Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of The Berlin Patient
Original Article: Brief Report Absence of Detectable HIV-1
Viremia after Treatment Cessation in an Infant
Deborah Persaud, M.D., Hannah Gay, M.D., Carrie Ziemniak, M.S., Ya Hui Chen, B.A., Michael Piatak, Jr., Ph.D., Tae-Wook Chun, Ph.D., Matthew Strain, M.D., Ph.D.,
Douglas Richman, M.D., and Katherine Luzuriaga, M.D.
N Engl J Med Volume 369(19):1828-1835
November 7, 2013
Very Early Triple-Drug ART Elicits “Potential Cure” in HIV-Infected Child Infant born to untreated HIV-infected mother at 35 wks’
gestation via spontaneous vaginal delivery[1]
– Maternal HIV infection identified during labor via ELISA and Western blot
– Infant HIV infection confirmed via HIV-1 DNA PCR, HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age[2]
– ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days
– ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age
– HIV-1 RNA undetectable by Day 30
– Mother removed patient from care at 18 mos of age
Specialized Studies to Assess Persistence of HIV-1 Infection in the Child.
Persaud D et al. N Engl J Med 2013;369:1828-1835
CURING HIV WILL BE DIFFICULT The State of the Art in HIV Cure Research— Hope or Hype
“Boston Patients” Two HIV+ patients who underwent allogeneic hematopoietic stem cell transplant
Both failed conventional therapy for lymphoma Reduced-intensity conditioning; no total body irradiation, no ATG Both had graph vs. host disease Donors CCR5 wild-type; recipients achieved full donor chimerism
No detectable HIV reservoirs in blood or rectal tissue (2-4 yrs after HSCT)
Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05. Henrich TJ, et al. J Infect Dis. 2013;207:1694-1702. Henrich T et al CROI 2014 #144LB
Long-Term PBMC DNA and CD4 Count Following RIC-alloHSCT
Henrich T, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract WeLBA05. HSCT: hematopoietic stem cell transplantation.
Patient A Patient B Post-HSCT Highly sensitive PCR-based chimerism
Host cells: 0.00041% to 0.00081% of
PBMCs
Host cells: 0.00035% to 0.00096%of
PBMCs
Immune response HIV-specific (INF-γ ELISpot) Other
None
None
None
CMV/EBV/ Influenza
ATI HIV plasma RNA PBMC DNA SCA* Proviral DNA*
7 weeks Not detectable Not detectable
-- --
15 weeks Not detectable Not detectable Not detectable Not detectable
Analytical Treatment Interruption
Patient
Tacrolimus GVHD txt during ATI
Analytical Treatment Interruption Patient
What Should “Cure” Look Like? • BMT too toxic, too dangerous, and too
expensive for most infected individuals
– For patients who need BMT, though, cure can and should be a goal
• Treatment for cure must be time limited, tolerable and have limited risk
• May be expensive – Modest success rate may be cost-saving
• Many hurdles but we have to start somewhere
Barriers to Cure • Low level viremia detectable in most ARV
treated patients[1]
• Residual viral replication?[2]
• Potential pharmacologic reservoirs[2]
• Latently infected cells[2,3]
• Resting CD4+ T cells which replenish [2,3]
• Other (potential) cell types [2,3]
• Long-lived cells (macrophage, microglia) [3]
• Failure of HIV-specific immunity and generalized immune dysfunction[4]
1. Palmer S, et al Proc Natl Acad Sci 2008 105:3879-84. 2. Johnston R, et al. J Int AIDS Soc. 2012;15:16. 3. Richman DD, et al. Science. 2009;323:1304-1307. 4. Kaufmann DE, et al. J HIV Ther. 2003;8:19-25.
Patients Treated During Acute HIV Infection Enhance the opportunity for Cure?
• Most individuals are infected with a single viral variant or a few highly related variants[1]
• CTL responses occur very early and can be robust • HIV-specific CD4-cell responses may be preserved by early
therapy[2]
• Persistent activation may be diminished • HIV reservoirs may be smaller and appears be inversely
related to replication AUC[3,4]
• Effective therapy stops viral evolution and appears to fix early variants in latent reservoir[5]
1. Abrahams M-R, et al. J Virol. 2009;83:3556-3567. 2. Oxenius A, et al. Proc Natl Acad Sci USA. 2000;97:3382-3387. 3. Ananworanich J, et al. 5th International Workshop on HIV Persistence During Therapy. 2011. Abstract 32. 4. Archin et al PNAS 2012 5. Anderson et al J Virol 2011
Reservoir Size in Treated AHI Model including VL, CD4 and latent cell decay
Archin … Margolis, Perelson PNAS 2012
clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013
Early Treatment of Pts With Acute HIV Infection Restricts Seeding of Reservoirs RV254/SEARCH 010: ongoing, prospective, open-label study of subjects
seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection)
Before ART, HIV reservoir seeding limited
– Integrated HIV DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts
– Lower infection frequencies of central memory CD4+ T cells vs other memory cells
After ART, decline in HIV reservoir size
– Integrated HIV DNA undetectable in PBMCs in 90% of pts at 1 yr
– Reservoir primarily in transitional and effector memory CD4+ T cells
Suggests very early ART may prevent seeding of reservoirs
Fiebig Stages
Fiebig I: RNA+, p24̶ neg, 3rd gen ELISA-neg
– Would not be detected by 4th gen ELISA
Fiebig II: RNA+, p24+; 3rd gen ELISA-neg
Fiebig III: 3rd gen ELISA+, WB-neg Ananworanich J, et al. CROI 2013. Abstract 47.
Fiebig I
Integrated HIV DNA at 24 weeks after ART
Not detected
Chronic HIV
Not detected
Fiebig III
Limited viral diversification in virus from plasma and resting CD4 cells 5 years after treated acute HIV infection.
Anderson et al J Virol 2011
Barriers to Cure • Low level viremia detectable in most ARV
treated patients[1]
• Residual viral replication?[2]
• Potential pharmacologic reservoirs[2]
• Latently infected cells[2,3]
• Resting CD4+ T cells which replenish [2,3]
• Other (potential) cell types [2,3]
• Long-lived cells (macrophage, microglia) [3]
• Failure of HIV-specific immunity and generalized immune dysfunction[4]
1. Palmer S, et al Proc Natl Acad Sci 2008 105:3879-84. 2. Johnston R, et al. J Int AIDS Soc. 2012;15:16. 3. Richman DD, et al. Science. 2009;323:1304-1307. 4. Kaufmann DE, et al. J HIV Ther. 2003;8:19-25.
– > 70% of “suppressed” patients have detectable viremia • Latent cells intermittently activate? • Persistent shedding from macrophage or other
long lived cells? • Ongoing replication?
Palmer et al, Maldarelli F, et al. PLoS Pathog. 2007;3:e46. Riddler et al CROI 2014
HIV-1 RNA Diversity
No Sequence Evolution after 7 years on cART Emergence of a Predominant Plasma Clone (PPC)
After Years on ART
0.005
Days on ART -20 0 20 40 60 10 1
10 2
10 3
10 4
10 5
10 6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
1500 1750 2000
HIV
-1 R
NA
(cop
ies/
mL)
Diversity (%
)
Start ART
2250
3.5 10 7
Kearney M, et al. Unpublished data used with permission.
0.0001 0.001 0.01 0.1
1 10
100 1000
10000
0 1 2 3 4 5 6 7 Time on HAART (years)
Freq
uenc
y (p
er 1
06 c
ells
) Resting CD4+ Cell Infection Extremely
Stable Despite ART
-
Time to eradication > 73.4 years
0.00001
1. Finzi D, et al. Science. 1997;278:1295-1300. 5. Siliciano JD, et al. Nature Med. 2003;9:727-728. 2. Wong JK, et al. Science. 1997;278:1291-1295. 6. Chun TW, et al. Nature Med. 1995;1:1284-1290. 3. Chun TW, et al. PNAS. 1997;94:13193-13197. 7. Chun TW, et al. Nature. 1997;387:183:188. 4. Finzi D, et al. Nature Med. 1999;5:512-517.
New Explanations for HIV Persistence
• Infection and persistence in long-lived CD4+ T memory stem cells1
• Homeostatic proliferation of infected cells may sustain the HIV reservoir2
• Integration of HIV into cancer genes which may
give infected clones a survival advantage3
1Lichterfeld M et al, CROI 2014, #54; 2Wagner T et al, CROI #138; 3Maldarelli F et al, CROI 2014, # 407LB
Other Challenges: •Clearance of infected cells •Clearance of virions •Complete block of new infection
Step 1: Eliminate Latent HIV Infection From Resting CD4+
Cells
Anti-latency therapy
1. Rong L, et al. PLoS Comput Biol. 2009;5:e1000533. 2. Lewin SR, et al. AIDS. 2011;25:885-897.
Potential Interventions to Disrupt Latency
Richman DD, et al. Science. 2009;323:1304-1307.
“Open” Histones Acetylated Histone tails
Reduced Higher Order Structure Access to Transcription Factors
Transcription Active
“Closed” Nucleosome Hypo-Acetylated Histone tails
Stable, Compact Chromatin Less accessible to Transcription Factors
Transcription Repressed
deacetylated
acetylated
HIV lives within chromatin: tipping the balance towards acetylation removes a restriction at the initiation of proviral expression
Schiralli Lester GM, et al. Mol Biol Int. 2012;2012:614120.
Single 400 mg VOR dose: Remeasure resting CD4+ T cell HIV RNA expression. Define potential for VOR to disrupt latency
Mean 4.8-fold induction (range 1.5- to 10-fold) All increases
significant (P < .01) No AE > Grade I
No AE due to
VOR Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt.
8
HIV
-1 g
ag R
NA
copi
es p
er w
ell
Archin NM, et al. Nature. 2012;487:482-485.
HDAC Inhibitors Selected for Clinical Trials in HIV+ Subjects on ART
Vorinostat SAHA
Romidepsin Panobinostat
Structure
Regulatory Status FDA Approved FDA Approved Phase 3
Indication CTCL CTCL MM/AML
Dose 400 mg QD PO 14 mg/m2 IV Days 1, 8, 15 (28 day cycle)
Pre-stimulation of CD8+ T Cells Enhanced CTL Responses
Shan et al Immunity 2012
Adapted from Freeman G. et.al., J Exp Med 2006.
Evidence supports blockade of the PD-1/PD-L1 pathway as a viable therapeutic strategy in chronic HIV infection
PD-L1
PD-1 PD-1 /-L1 Blockade
• Persistent antigenemia leads to T cell exhaustion
• PD-1 is a key inhibitory receptor affecting T-cell response – Elevated on virus-specific T-
cells in chronic HIV; – seen on both CD4+ and CD8+
subsets; – cells display exhausted
phenotype ex vivo • Blockade of PD-1/PD-L1
– Restores HIV-specific immune functions in vitro and ex vivo
– Reduces viremia and prolongs survival in animal models in vivo
Barrier to HIV eradication: T cell exhaustion and the PD-1 pathway
52
PD-L1 blockade in ARV suppressed SIVmac251-infected Rhesus Macaques
Hypothesis: – Treatment of ARV-suppressed SIV infected macaques with αPD-L1 should:
– restore SIV-specific T cell function. Subsequently, this may: – reduce the latent SIV reservoir – lead to host control of virus following interruption of ARV
1. Virus-specific T cell functionality, 2. Cell-associated viral DNA (latent reservoir) in tissues and periphery, 3. Virus recrudescence after cessation of ARV treatment.
Objectives: – Determine whether multiple doses of BMS-936559 affect:
PD-L1 blockade
Start ARV
BMS-936559 (8) Isotype control (5) 5 X 10mg/kg
6 weeks
ARV TI
Viral load rebound off ARV
Study design: SIV Infection
2 weeks
Kinetics of viral load rebound post-treatment interruption
• Half of BMS-936559-treated animals had rebound similar to isotype-treated animals • BMS-936559-responder group remained below 1000 cp/mL for >8 weeks • Two had undetectable VL for 3-4 weeks
LOQ at 50 SIV RNA copies/mL *
J. Whitney S. Sanisetty
BMS-936559
Isotype
ACTG 5326
Safety and immunotherapeutic activity of an anti-PD-L1 antibody (BMS-936559) in HIV-1 infected subjects on suppressive
ART: pilot phase II, 24 week, double-blind, placebo-controlled, ascending single
blood and systemically - Env-specific immunotoxin further
reduced HIV RNA by • Up to 1000-fold in individual tissues • 0.8 log10 copies/mL systemically
- Mechanism of reduced HIV RNA • Loss of productively infected cells
Denton PW, et al. 7th IAS Conference. Kuala Lumpur, 2013. Abstract TuAA0101.
No ART (n=68 samples)
10 mice
Log 1
0 HIV
RN
A co
pies
per
10
5 CD
4 or
Tot
al T
hym
ocyt
es
HIV RNA Levels: All Tissues
ART (n=99 samples)
15 mice
ART + 3B3-PE38
(n=40 samples) 6 mice
-2.9 log10*
*P<0.001.
-2.1 log10*
-0.8 log10*
Additional Cure Strategies
• Genetic modification of CD4+ cells to limit or stop HIV replication[1]
– eg, Zinc finger nuclease “excision” of CCR5 gene[1]
• Specific activation of HIV-infected resting memory cells using targeted nano-particles[2]
• IL-7 or IL-16 with ARV intensification[3] • Reduce residual activation/inflammation and
limit replication in tissue??
1. Berger EA. Curr Opin HIV AIDS. 2011;6:80-85. 2. Wayengera M. HIV AIDS Rev. 2011;10:1-8. 3. Beq S, et al. Eur Cytokine Netw. 2004;15:279-289.
Cure Studies In ACTG HIV-1 infected patients suppressed on ART
• A5315 – Single dose romidepsin
• A5326 – Anti-PD-L1 antibody – Single infusion
• A5337 – Sirolimus (rapamycin)
Will HIV Infection be Curable? • HIV-1 can be cured in rare situations
– Bone marrow transplant (with resistant cells?) – Very early infection in infants (and maybe adults?)
• Substantial barriers to scalable curative treatments exist – Latently infected cells that sustain themselves – The possibility of ongoing replication – Inflammation may contribute to both of the above – Tissue or cellular sanctuaries (especially brain?)
• However – initial steps have been taken • Improvement in assays, medications and medical technology • Modestly effective therapy (30% cure) can be very cost
effective
Acknowledgements • David Margolis • JoAnn Kuruc • Victor Garcia • John Mellors • Mike Cohen • Mary Kearney • Joe Wong • Bob Siliciano • Steve Mason • Steve Deeks
Volunteers across all cure studies for their altruism and bravery
Thanks to all the patients participating in cure research!
“Post-Treatment Controllers” in ANRS Visconti Cohort 14 HIV patients whose viremia remained controlled for several yrs
after the interruption of prolonged cART initiated during primary infection
Pts standard cART available at time of tx (for some, all-NRTI tx)
HIV-1 RNA became undetectable in median of 3 months (0.5 to < 8 months)
Median cART duration: 36.5 months
PTCs lacked protective HLA-B alleles overrepresented in spontaneous HIV controllers (HICs)
Sáez-Cirio´A, et al. . Plos Pathogen. 2013;9: e1003211.
clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013
Long-Term Control of Viral Replication After Treatment During Primary Infection
Sáez-Cirio´A, et al. . Plos Pathogen. 2013;9: e1003211.