microbicides: state-of- the-art 2010 - virology...

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

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



Biology of HIV acquisition in women



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


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



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



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.


Brief history of microbicide development



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)



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)


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)


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?



Lessons learnt in the microbicides field thus far



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



Current pipeline



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


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)


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


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



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.



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


‘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



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)


Research needs



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



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


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


27Presented at the 5th INTEREST Workshop25-28 May 2010, Maputo MozambiquePresented at the 5th INTEREST Workshop25-28 May 2010, Maputo Mozambique

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