HIV- cure?
Graham P Taylor Section of Infectious Diseases
Highly effective anti-retroviral therapy 100,000
Combivir/nevirapine Kivexa/nevirapine 10,000
1,000
100
10 1997
1999
2001
2003
2005
2007
2009
2011
2013
Life expectancy 2013 HIV infection 2010 Male 75 yrs Fig. 2 . Projected range of outcomes in terms of mortality and diagnosis status for 30-year-old MSM infected in 2010.(a) Projected range of outcomes under the assumption of a high rate of diagnosis over 70 years. (b) Projected range of outcomes under the assumption of a low rate of diagnosis over 70 years. The rate of diagnosis was altered such that the median CD4 cell counts at diagnosis were 140 and 432 cells/[mu]l, respectively, for low and high diagnosis rates. A table of the actual numbers used to generate these figures can be found in the Supplementary Material section (http://links.lww.com/QAD/A193).
Projected life expectancy of people with HIV according to timing of diagnosis. Nakagawa, Fumiyo; Lodwick, Rebecca; Smith, Colette; Smith, Ruth; Cambiano, Valentina; Lundgren, Jens; Delpech, Valerie; Phillips, Andrew AIDS. 26(3):335-343, January 28, 2012. DOI: 10.1097/QAD.0b013e32834dcec9
Š 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
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HIV eradication Pubmed search 17th September 2013 915 articles 357 review articles
Stem Cell Transplantation in HIV infection 40 yr white male HIV-1 infected 10 yrs, Atripla 4 years, HIV <50, CD4 415 Diagnosed AML â&#x20AC;&#x201C; chemotherapy, Relapsed @ 7 months Conditioning regimen Allo STC with CD34+ peripheral blood stem cells CCR5 D32-/HAART continued until 1 day before procedure anti-thymocyte globulin, ciclosporin, mycophenolate AML relapsed after 332 days Re-induction (Cytarabine, gemtuzumab, 200cGy irradiation) - Second transplant day 391 â&#x20AC;&#x201C; same donor Hutter et al NEJM 2009;360:692-8
Hutter et al NEJM 2009;360:692-8
Clinical Course and Viraemia
Immune responses to HIV post transplantation
T-spot – single peptide
Hutter et al NEJM 2009;360:692-8
Lane Lane Lane Lane
1 2 3 4
- Positive control – Pre STC – Post – Day 623 - Negative control
BMT/STC - not a new idea Could bone marrow transplantation cure AIDS?: review- HuĹžiÄ?ka I Medical Hypotheses 1999;52:247-257 Since 1982 - 32 patients underwent BMT. HIV was eradicated in two Syngeneic bone marrow transplantation and adoptive transfer of peripheral blood lymphocytes combined with zidovudine in human immunodeficiency virus (HIV) infection - sixteen patients Ann Intern Med. 1990 Oct 1;113(7):512-9.
CCR5 D32 -/- stem cells = NEW
What is cure?
Biological cure â&#x20AC;&#x201C; eradication of every single infected cell (as illustrated by the German Transplantation case) When? How tested?
Eradication of HTLV-1 following BMT We describe an Afro-Caribbean female with very poor prognosis ATL who underwent chemotherapy with a 4 d infusion schedule of cyclophosphamide, doxorubicin and etoposide, followed by successful allogeneic bone marrow transplantation (BMT) from her HTLV-1-negative histocompatible sister. The patient remains in complete remission 23 months after BMT and has 100% donor haemopoiesis with no evidence of HTLV-1 infection on PCR testing. We suggest that allo-BMT can prolong disease free survival or may even be curative in HTLV patients Borg A et al, BJH 1999
Patient reviewed in 2013 â&#x20AC;&#x201C; ATLL cured. HTLV-1 detected in PBMCs
What is cure?
Functional cure â&#x20AC;&#x201C; an inactive carrier state with no viral replication in the absence of therapy When? How tested?
How can Functional Cure be achieved? 1. Early intensive therapy
48 weeks of early HAART in adults delays need for subsequent HAART
Fidler S et al, SPARTAC, NEJM 2013;368:207-217
48 week early HAART in children delays time to start life-long therapy Start ART
Proportion starting cont. ART
1.0
Restart ART after interruption
0.75
0.5 ART Def ART-40W ART-90W
0.25
10
0
Number at risk: ART Def 125 126 ART-40W 126 ART-96W
48 13 105 126
96 144 192 Weeks since randomisation 0 38 126
0 31 54
0 27 43
240 0 18 24
CHER: Children with HIV Early Antiretroviral Therapy, Cont: continuous, Def: deferred, HIV: human immunodeficiency virus, W: weeks Violari et al. IAS 2007. Abst. WESS103.
Proportion with clinical failure
Progression to severe CDC B or CDC C or death 1.0
ART Def ART-40W ART-90W
0.75
HR (95% CI) relative to ARTDeferred ART-40W: 0.5 (0.3 – 0.8, p=0.005) ART-96W: 0.4 (0.3 – 0.7, p=0.0003)
0.5
0.25
0.00
0
Number at risk: ART Def 125 126 ART-40W 126 ART-96W
48 79 106 105
96 144 192 Weeks since randomisation 72 85 96
71 83 89
70 82 88
240 57 67 68
CDC-B: Centers for Disease Control classification system for HIV infection: moderately symptomatic, CDC-C: severely symptomatic, CI: confidence interval, Def: deferred, W: weeks Cotton et al. CROI 2012. Abst. 28LB.
Immediate intensive therapy in a new born achieved ‘Functional cure’ Born at 35/40 (2.5kg) normal SVD
No antenatal care Rapid HIV test (performed during labour) reactive
Precipitous delivery – no ART administered Baby transferred to tertiary centre age 30 hours ZDV/3TC/NVP started by 31 hours
Persaud et al. CROI 2013. Abst. 48LB
‘Functional cure’ 100,000
HIV RNA copies/ml plasma
Viral load
10,000
ART/care discontinued
1,000
100
10
0
5
10
15
Months Persaud et al. CROI 2013. Abst. 48LB
20
25
30
Virological studies to detect residual HIV in this very-early treated child Proviral DNA
Copies/ 10*6 cells
Cells tested /well (No replicates pos)
PBMC
24/12 26/12
<2.7 4.2
122,000 (0/2) 133,000 (1/6)
Resting CD4 T-cells
24/12 26/12
<3.5 <2.5
96,500 (0/3) 134,000 (0/6)
Enriched for activated T-cells
24/12 26/12
< 2.2 <2.6
154,000 (0/6) 130,000 (0/6)
Monocyte-derived adherent cells
24/12 26/12
37.6 <11.5
14,300 (1/3) 29,000 (0/6)
HIV RNA Plasma
24/12 26/12
1 copy/ml <2 copies/ml
n/a n/a
Infectious virus from resting CD4+
24/12
Not recovered
n/a
Persaud et al. CROI 2013. Abst. 48LB
Post-Treatment Controllers 14 patients from the Viro-Immunological Sustained Control after Treatment Interruption (VISCONTI) study Diagnosed with Primary HIV Infection (1.1 to 2.1 months after exposure) 1996 - 2002 Fully suppressed HIV within 3 months (median cART = 36.5 months) Post-Treatment interruption â&#x20AC;&#x201C; viral control for median 89 months (8/14 always <LDL; 6/14 intermittently detectable)
Saez-Cirion et al PLoS Pathogens 2013
Are the PTCâ&#x20AC;&#x2122;s just treated elite controllers? Median HIV viral load 5 log, CD4 502 ( cf 3 log and 794 in PHI achieving spontaneous viral control) No more likely to carry protective alleles (HLA B*57 and HLA B*27) than the general population; high frequency of risk alleles (HLA B*07 and HLA B*35) Weak or barely detectable HIV-specific CD8 T-cell responses during viral control period Low levels of CD8 activation (HLA DR and CD38 expression)
Saez-Cirion et al PLoS Pathogens 2013
The PTCâ&#x20AC;&#x2122;s differ significantly from elite controllers Median HIV viral load 5 log, CD4 502 ( cf 3 log and 794 in PHI achieving spontaneous viral control) No more likely to carry protective alleles (HLA B*57 and HLA B*27) than the general population; high frequency of risk alleles (HLA B*07 and HLA B*35) Weak or barely detectable HIV-specific CD8 T-cell responses during viral control period Low levels of CD8 activation (HLA DR and CD38 expression)
Saez-Cirion et al PLoS Pathogens 2013
How common might PTC be? Probability of maintaining virological control 15.3%
Based on initiating treating during PHI (<6 months from exposure) & Treated for at least one year & Undetectable HIV viral load
Saez-Cirion et al PLoS Pathogens 2013
Clearly this doesn’t happen with later treatment What can be done in ‘normal’ circumstances
1. Early intensive therapy 2. Intensification Double intensification with raltegravir and maraviroc does not reduce HIV proviral load in PBMCs Katlama C et al, CROI 2013
SIV in macaques treated with tenofovir, FTC, Darunivir/r, raltegravir and maraviroc had RNA <3 /ml and DNA < 2/100,000 PBMCs (and rectal mucosa and lymph nodes) Shytai IL et al PLoS Pathogens 2012 8e:1002774
What can be done in â&#x20AC;&#x2DC;normalâ&#x20AC;&#x2122; circumstances
1. Early intensive therapy 2. Intensification 3. Expose the latent retrovirus
Unmask latent infection
Anatomical hidden reservoirs â&#x20AC;&#x201C; gut, genitalia, brain poor HAART penetration Functional reservoirs - long-lived latently infected cells HIV infected central memory cells (TCM) HIV infected transitional memory cells (TTM) HIV infected T memory stem cells (Tscm) high proliferative potential NEW Buzon M et al CROI 2013
Unmask latent infection
Histone deactelylase inhibitors Sodium valproate Vorinostat B-catenin inhibitors Stops stem cells from differentiating into memory cells
T-cell activation IL-2 Interferon-a2b IL-7 â&#x20AC;&#x201C; not effective in ERAMUNE
Histones
Histone acetylation and deacetylation
Efficacy of Histone deacetylase inhibitors in BLV 40.000 40000
1600 WBC
p24 cells
number of cells (mm3 of blood)
B/CD11b 30.000 30000
1200
20.000
800
20000
10.000
400
10000
Time (days) Time (days)
0
0
0
1/12/03 -1
16/12/03 14
31/12/03 29
15/1/04 44
30/1/04 59
14/2/04 74
-1 14 29 44 59 74 1/12/03 16/12/03 31/12/03 15/1/04 30/1/04 14/2/04
Time (days)
Response of Bovine Leukaemia in sheep treated with 10g infusion of Sodium valproate on alternate days for 40 days (80mg/kg) (max usual dose in humans for epilepsy = 2.5g/day)
Combined zidovudine and valproate in STLV-1 infection Afonso et al, Blood Nov 2010
Effect of valproate on HTLV-I in patients with HAM TSP
Copyright Š2007 American Society of Hematology. Copyright restrictions may apply.
â&#x20AC;&#x2DC;Cure therapies in trial
Target
Approach
Phase
Zn Finger nuclease mediated gene disruption
Gene Therapy
I
To induce CCR5 deletion
Viral Transcription induction
HDI
I/II
Valproate Vorinostat
Viral replication
Intensification
II
Maraciroc/ Raltegravir
ImmunomodulatIon
Activation and suppression
I/II
IL-7 Sirolimus
Summary Life expectancy for HIV infected patients accessing care is approaching normal Bone Marrow/Stem cell transplantation may in some cases lead to HIV eradication but has high morbidity/mortality and cost. Intensification of therapy in established infection â&#x20AC;&#x201C; conflicting data Treating early in primary HIV infection has general health benefits and in a minority appears to result in functional cure â&#x20AC;&#x201C; applicable to very small numbers of patients Unmasking the retroviral reservoirs remains an attractive but unproven option