Community Issues And Needs Associated With Microbicides Clinical Trials
Microbicides: State-of- the-Art 2010 - Virology...
Transcript of Microbicides: State-of- the-Art 2010 - Virology...
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Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Microbicides: State-of-the-Art 2010
INTEREST workshop, 28 May 2010
Janneke van de Wijgert, Associate ProfessorAcademic Medical Center of the University of Amsterdam
Amsterdam Institute for Global Health and Development
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1Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Outline
• Brief review of biology of HIV acquisition in women
• Brief history of vaginal microbicide development
• Lessons learnt in the microbicides field thus far
• Current pipeline
• Research needs
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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2Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Biology of HIV acquisition in women
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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3Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Early events in vaginal transmission (reviewed in Haase, Nature, 11 Mar 2010)
• Cell-free HIV crosses mucosal epithelium within hours
• One single HIV virus genotype establishes a small founder
population of infected cells
• Week 1: dissemination to lymphoid tissue only possible
after local expansion
• Week 2: replication in lymphoid tissues explodes
• Week 3/4: stable lower levels of replication; reservoirs
established; first depletion of CD4+ T cells
• CD8+ T cell response does occur but ‘too little, too late’
• Rectal/oral transmission: no local expansion step?
• Cell-associated HIV transmission difficult to study in NHP
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4Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Crossing the mucosal tissue barrier
• Endo/ectocervix most vulnerable but initial foci of infection
also observed in vagina when inflammation present
• Mucus is protective: amount and consistency depend on
menstrual cycle and co-infections
• Normal lactobacilli-dominated vaginal flora is protective
• Initial target cells:• CD4+/CCR5+ T cells (but not fully activated)
• DCs (including LCs) and macrophages with CD4, CCR5, DC-
SIGN and/or Langerin receptors; but CD4+/CCR5+ T cells
outnumber them 4:1
• Role of LCs still unclear – they may block infection in some
circumstances but facilitate in others
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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5Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Innate mucosal immune defenses
• HIV is recognized by PAMPs receptors on mucosal epithelial
cells:
• Production of defensins/anti-microbial peptides, SLPI,
lactoferrin, lysozyme, cytokines/chemokines
• Complement activation
• Recruitment of immune cells
• Immune cells produce interferons, other cytokines, and –
eventually – antibodies against HIV
• Paradoxal effects:
• Transmission probability is low because of these defenses
• But defenses can be overcome due to increased availability
of target cells for HIV and efficient cell-to-cell spread
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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6Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
How could microbicides work?(Shattock & Moore, 2003)
More recently: Inhibiting production of viral particles at later stages (e.g.
protease inhibitors) may also work by aborting initial foci of infection prior to
dissemination.
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7Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Brief history of microbicide development
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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8Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Nonoxynol-9
• Been on market for 25+ years as a spermicide but had never undergone rigorous safety testing
• COL1492 trial: Increased HIV acquisition in women who used it more than 3 times per day (van Damme, Lancet 2002); also increased incidence of lesions with epithelial disruption
• Many other detrimental effects, including poor therapeutic index (cytotoxicity), strong inflammatory responses, increased epithelial permeability, sloughing of epithelial cells, and disruption of vaginal flora (Hillier, JAIDS 2005)
• Now used as a ‘positive control’ in preclinical experiments• Other detergents also no longer considered (e.g. Savvy)
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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9Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Polyanions
• Ineffective but safe in Phase 3 trials: Carraguard (Skoler,
Lancet 2008), PRO-2000/5 (McCormack, CROI 2010)
• Ineffective; perhaps not safe: Cellulose Sulfate (van Damme, NEJM 2008)
• During/after trials, experiments showed that polyanions:
• Cannot penetrate the mucosal tissue and are therefore
not present at the site of viral entry into target cells
• Block gp120, CD4, CXCR4, but not/less efficiently CCR5
and DC-SIGN; are not virucidal for R5 viruses (Shattock, Nat Rev Microbiol 2003 & 2006; Fletcher, Retrovirol 2006; Huskens, Antiviral Res 2009)
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10Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Polyanions - continued
• Enhance HIV infection at low doses (0.3–3 μg/ml)
and reduce infection only at higher doses (Tao, ARHR 2007; Turville, PL0S One 2008)
• Disrupt tight junctions (but reports are
inconsistent) (Mesquita, JID 2009)• Are much less effective in the presence of vaginal
fluids and semen (Neurath, BMC Infect Dis 2006; Patel, JID 2007; Keller, PLoS One 2010)
• Are not inflammatory (Keller, AIDS 2007; Bollen, JAIDS 2008)
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11Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Buffers of vaginal pH
• Ineffective but safe in Phase 2B trial: BufferGel (Karim, CROI
2009)
• ACIDFORM in Phase 1• No detrimental effects reported but mechanism of action is
too non-specific and not sufficiently potent?
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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12Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Lessons learnt in the microbicides field thus far
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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13Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Lessons learnt
• Active ingredients must be HIV-specific and potent
• Advance only ‘best in class’ products
• More emphasis on combination products to increase
potency and minimize drug resistance
• PK/PD matters, including microbicide activity in presence of
mucus, cervicovaginal fluids, and semen
• Safety matters: good therapeutic index; no epithelial
disruption; no increase in HIV target cells; no inhibition of
L. crispatus and L. jensenii in vaginal flora
• Formulation matters (osmolarity, pH, etc)
• Adherence in clinical trials matters
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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14Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Current pipeline
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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15Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Topical use of antiretroviral drugs
Phase 1StarPharmagp120 blockerVivaGel
PreclinicalBMS/IPMgp120 blockerDS003 (BMS793)
PreclinicalMerck/IPMCCR5 blockersM167, M872, M882
PreclinicalMintakaFoundation
CCR5 blockersPSC-RANTES analogues
PreclinicalMerck/IPMgp41 blockerL’644 peptide
PreclinicalPfizer/IPMCCR5 blockerMaraviroc
Phase 1Pop CouncilNNRTIMIV-150 (+ Zinc acetate) gels
Phase 1/2Cellegy/ConradNNRTIUC-781 gel
Phase 3; starts 2011
Tibotec/IPMNNRTIDapivirine ring/gel
Phase 2B; reports July 2010
Gilead/NIH/IPM
NRTITenofovir gel
StatusSponsorsMechanismCompound
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Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Tenofovir: CAPRISA 004 and VOICE
• Both Phase 2B trials in African settings
• CAPRISA 004 (tenofovir vaginal gel):• 2 doses within 12 hours before and 12 hours after sex• Targeting 92 HIV endpoints; reporting July 2010
• VOICE (tenofovir vaginal gel + tenofovir oral pills + Truvada oral pills):• 1 daily dose• Targeting 94 HIV endpoints; reporting 2013
• Daily oral PrEP: Several efficacy trials ongoing with tenofovir and/or Truvada in different populations (first results to be reported in 2011)
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17Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
What if positive results?
• If CAPRISA 004 shows effect: A Phase 3 of tenofovirgel use should be conducted a.s.a.p. to enable registration; VOICE dosing is different and also Phase 2B. Compare coitally-dependent with daily use?
• If oral PrEP shows effect, continue work with topical applications because:• Tenofovir/Truvada increasingly used as first-line
therapy• Improve adherence (ring, injections, implants)• Evaluate lower doses to minimize toxicity
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18Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Dapivirine (TMC-120)• Dapivirine gel and matrix ring are ready for Phase 3; IPM is also
developing other formulations (tablet, film, soft-gel capsule)
• Phase 3 protocol currently being developed
• Projected start-date 2011
• Current IPM priorities:
• Dapivirine ring
• Dapivirine gel
• Dapivirine-maraviroc ring
• Dapivirine-maraviroc gel
• Maraviroc-tenofovir film
• Dapivirine-DS003 vaginal tablet
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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19Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Other ARVs under consideration
• HIV protease inhibitors (CHAARM): Would only work if aborting the infection early, prior to dissemination to the lymphoid tissues, is sufficient for protection. Appears to work in PEP.
• HIV fusion and integrase inhibitors (CHAARM)
• Combinations of HIV-specific compounds (IPM, CHAARM): To minimize HIV drug resistance; perhaps maximize efficacy by combining different mechanisms of action.
• Combinations with contraceptive compounds (IPM, Pop Council): To allow for dual protection.
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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20Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Maximizing potency and minimizing HIV drug resistance
• Endocervical and rectal explant studies (Herrera et al, Microbicides 2010)
• 2 antiretroviral drugs – significant gain
• 3rd drug – some additional gain
• 4th drug – no additional gain
• Many combinations presented at M2010: synergies
were common in preclinical experiments, especially
with drugs from different drug classes
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21Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
‘Live’ microbicides
• Genetically enhanced Lactobacillus crispatus or jenseniiproduce anti-HIV proteins
• In development:
• MucoCept (Osel Inc, USA)
• LACTIN-V (CTV-05)
• MucoCept showed 57% protection in NHP repeated
challenge model
• Early clinical studies in women ongoing and planned
• But: regulatory issues are complex
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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22Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Other preclinical compounds
• Monoclonal neutralizing antibodies / plantibodies / nanobodies
• Flavonoids (entry inhibitors derived from green and black tea)
• Griffithsin (entry inhibitor derived from red algae)
• Retrocyclins (antiretroviral peptides)
• Small interfering RNA (gene silencing)
• Glycerol monolaurate (inhibits inflammatory response caused by HIV-exposed epithelial cells)
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23Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Research needs
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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24Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Use expanded biological knowledge for rational microbicide design
• Block CD4, CCR5, and/or DC-SIGN receptors (but not
Langerin) to prevent entry – still not clear which
receptors are most important
• Block HIV replication to prevent productive infection
in genital tract and dissemination to lymphoid tissues
– what about migrating DCs?
• Avoid detrimental effects of candidate products on
the vaginal micro-environment – but VME needs to
be much better characterized
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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25Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Incorporate the vaginal micro-environment in microbicide safety testing
• Need better biomarkers for product safety to prevent
increased HIV acquisition in Phase III trials
• Relevance of currently used cell systems and animal
models is not known
• Pelvic exams and colposcopy could not predict safety
• So far, cytokine profiles do not show clear patterns
• Cannot fully validate biomarkers until a safe and
effective product has been identified
• Closely monitor PK/PD and HIV drug resistance
• Continue research on long-acting formulations and novel
adherence strategiesPresented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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26Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
Ongoing microbicide research funded by Europe
• EDCTP microbicide/vaccine trial preparedness in SSA
• EDCTP biomarkers study
• EUROPRISE – networking, PhD (basic science)
projects
• CHAARM – microbicide product development
• Since closure of MDP 301, no large clinical trials,
with exception of trials via IPM
Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique
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27Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo MozambiquePresented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique