Transcript Slide 1

Understanding mucosal immunity and
HIV transmission: the way to new
prevention technologies
AIDS 2010, Vienna
Robin Shattock
Centre for Infection, Division of Cellular & Molecular Medicine, St George’s University of
London, UK
Mechanisms of transmission
Infection of macaques after vaginal exposure to cell-associated simian immunodeficiency
virus. Sallé B, Le Grand R.J et al. Infect Dis. 2010 ;202(3):337-44.
Drug penetration
For any prevention technology, success will depend on
maintaining protective inhibitor concentrations at the
mucosal portals of entry.
State of the pipeline for microbicides.
•First generation concepts (successfully tested) but lacked potency
•Drive for more potent products (Anti-Retroviral ARV) products
•Systematic testing of the biological plausibility of different targets in
primate models
•Drug distribution and tissue activity studies in NHP and human studies
(PK/PD)
•Proof of concept for first ARV candidate (TFV gel)
•Current need to better understand dosing relationship (coital/non
coital)
•Prioritization of new formulations that maximize adherence
•Development of combination products will increase in importance
•Prioritize (product/dosing) and acceleration of additional clinical trials
Microbicide
Time
Inhibit entry
Hours
Inhibit reverse
transcription
Days
Inhibit
Integrase &
protease
Viral binders
CCR5 antagonists
NRTI (TDF)
NNRTI (DPV/UC781)
Integrase inhibitors
Protease inhibitors
Weeks
PrEP
Haase T., Ashley, 11 March 2010, Nature, v. 464, p. 217-223.
Building on the ART of HIV-1 therapy –
and success of CAPRISA 004
Nucleos(t)ide Reverse Transcriptase
Inhibitors (NRTIs)
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)*
Lamivudine (3TC)*
Stavudine (d4T)
Tenofovir (TDF)*
Zalcitabine (ddC)
Zidovudine (ZDV)
3TC/ABC
3TC/ABC/ZDV
3TC/ZDV
FTC/TDF*
Nonnucleoside RTIs (NNRTIs)
Delavirdine (DLV)
Efavirenz (EFV) , MIV-150*
Nevirapine (NVP), Dapivirine (TMC-120)*
Multiple Class Combinations
Protease Inhibitors (PIs)
Amprenavir (APV)
Atazanavir (ATV)
Darunavir (DRV) *
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/r) *
Nelfinavir (NFV)
Ritonavir (RTV) *
Saquinavir (SQVhgc) *
Tipranavir (TPV)
Fusion Inhibitors (FIs)
Enfuvirtide (ENF)
Chemokine Receptor 5 (CCR5) Inhibitors
EFV/FTC/TDF
Integrase Inhibitors
Raltegravir*
Maraviroc (MVC)*
*current candidates for PrEP and/or microbicides
Compounds protective in monkey models
R5 virus challenges
b12: MAb, SHIV-162P4, vaginal.
PSC-, 6P4-, 5P12-RANTES: Modified chemokine, SHIV-162P3, vaginal.
BMS-806: Small molecule to gp120, SHIV-162P3, vaginal.
C52L: Peptide to gp41, SHIV-162P3, vaginal.
T1249: Peptide to gp41, SHIV-162P3, SIVmac251, vaginal.
CMPD 167: Small molecule to CCR5, SHIV-162P3, vaginal.
Maraviroc: Small molecule to CCR5, SHIV-162P3, vaginal.
TDF (tenofovir gel): NRTI, SIVmac251, vaginal + rectal (up to 3 days post application) *.
L-870812, Integrase inhibitor, SHIV-162p3, vaginal.
NCp7 Nucleocapsid protein inhibitors (ZFI), SHIV-162P3+SHIV89.6, vaginal
Griffithsin: Protein lectin, SHIV, SIVmac, vaginal
•>20 studies
PC-815: Carrageenan/MIV-150 (NNRTI), RT-SHIV, vaginal
demonstrating
PC-1005: Carrageenan/MIV-150/ZInc, SHIV-RT, vaginal
X4 virus challenges
CAP: Polyanion, SHIV-33A, vaginal.
Cyanovirin-N: Protein lectin, SHIV-89.6P, vaginal + rectal.
SPL7013: Polyanion, SHIV-89.6P, vaginal
PRO-2000: Polyanion, SHIV-89.6PD, vaginal.
AMD3465: Small molecule to CXCR4, SHIV-189.6P, vaginal.
biological plausibility
•TFV gel now becomes
the bench mark.
•PK now needs to be
related to protection
Drug distribution and tissue activity studies seen as critical (PK/PD)
•Non human primate studies are now being configured to relate drug distribution
(Systemic, tissue, topical) to protection, providing a bridge to human studies
(pharmacokinetics (PK)) – how much drug is needed and where is it need to provide
protection?
•Parallel human studies are being performed to determine drug distribution following
application
•Most importantly, studies to determine tissue drug activity are being developed as
potential surrogate markers of protection (pharmacodynamics (PD)) – is the drug active at
the site were it should work
These are now seen as critical tools for product development
Application of the tools to TFV gel may be critical in
determining dosing regimes (coital/daily) and providing a
bench mark for other candidates
Prioritization of new formulations that maximize adherence
Prevention
Prior to
Exposure
Prior to Exposure
Rights driven
behavior change
VCT
STI treatment
Male circumcision
Pre-exposure
prophylaxis
Vaccines
Time of
Exposure
Treatment
and Care
Point of Transmission
Male and female
Condoms and lube
Cervical barriers?
Microbicides
Anti-retroviral
therapies
Opportunistic
infection
therapies
Prevention for
positives
Basic care
Education and
behavioral
change
Target cells must be protected
at the time of viral exposure
Critical parameters
– turnover of target cells entering and exiting mucosal
tissue in steady state and inflammation
- Potential entry of infected donor cells
1% gadolinium 1:100 in a sterile system with Dextrin sulphate gel, 2hrs post application (C. Lacey, Imperial College)
Coitally dependent, daily and sustained delivery
Sex acts, A, B, C
Vaginal ring reservoir
Semi-solid formulation,
coitally independent
Gel formulation,
coitally dependent
Adapted from Karl Malcolm - Queen’s University Belfast
Gel formulation,
coitally dependent
Biological questions raised by CAPRISA 004
• 54% protection in those with >80% compliance.
• Why not higher? – if measured compliance = real compliance
• Concentration of drug
– would more be better (more TDF, or additional drug combinations)
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Spacing of dosing (BAT 24 – pre and post)
Better adherence – alternative dosage forms/regimes
Target cell turnover (inflammation, co-infection)
Potential differences in efficacy against cell free vs cell associated
virus?
Facing the problem of resistance to microbicides:
when and how?
• Risks of resistance for topical ARV microbicdes are hypothetical.
• Risks may differ between products
• Topically applied drug may prevent transmission of resistant
isolates
• Resistant virus may have reduced fitness for transmission
• In a clinical trial the risk/benefit ratio is likely to be low
• No resistance seen in CAPRISA 004 trial
– but too early to asses impact on treatment
• ARV approach likely be initially implemented as a prescription
only
• Resistance continued to be monitored with wider introduction
• If identified, enhanced emphasis would be placed on
combinations
Product prioritization
•Mechanism of action: NRTI, NNRTI, CCR5 PI, II etc
•Stage of development – human data, manufacture
•Appropriateness for combinations
•Pharmacokinetics/pharmacodynamics (PK/PD)
- NHP/human – TFV comparison
•Ability to be delivered in multiple dosage forms
Sustaining Accelerating progress in a changing prevention landscape
HSV-2 Treatment
- Infectiousness
Index Partner
Treatment
Vaccine Prime/Boost
Thailand
Vaccine - DNA
Prime/Ad5 Boost
US
Microbicide BufferGel,
PRO2000
Microbicide Tenofovir Gel
CAPRISA 004
2009
New
Vaccine
concept(s)
Vaccines
Microbicide Dapivirine
gel & ring
Microbicides
Oral TDF &
Truvada &
Tenofovir gel VOICE
Microbicide PRO2000
Oral TDF -MSM
US (Ph II)
Treatment
Oral Truvada MSM (iPrEx)
Oral TDF,
Truvada Partners PrEP
Oral Truvada –
Heterosexual
Botswana
Oral Truvada FemPrEP
Oral TDF - IDU
Thailand
TMC 278 UK (Ph I/II)
2010
2011+
PrEP
2015+
ARV protection
Immunological protection
Can they be combined?
How might new prevention options work
together?
Combining microbicides or PreP with vaccines may deliver even
better protection – the window for placebo controlled trials my be closing
• Provides protection during the immunization period
• Reduces infectious challenge.
• Boosts local immunity (virus/antigen)
• Broadening localized immunity through protected exposure to
prevalent virus.
• Converting high risk challenge to low risk challenge (RV144)
• Vaccine induced immunity may cover intermittent compliance,
break through virus and prevent resistance evolution
Pathways to reversing the epidemic
A comprehensive approach to prevention
ARV microbicide
ARV Prep
HIV incidence
Partially effective
vaccine
highly effective vaccine
Time
Thank you for your attention
NIH
U19 award AI060614–01