HIVCureResearchintheUK

Doweneedacureandwhatarewedoingaboutit?

DeathsduetoHIVAIDS2010

•  Sincethebeginningoftheepidemic30yearsago(June1981)almost60millionpeoplehavebeeninfectedwithHIV

•  25millionpeoplehavediedfromHIVrelatedcauses:1.8milliondeaths/year

•  2.7millionnewinfecQonsayear(40%inages15‐24years)

WHATAREWEDOINGTOSTOPTHIS?

AnQretroviraltreatment(ART)works!!

Butwecan’tdeliverittoallthoseinneed

Treatmentworkssowhyisn’teveryoneonit?

•  ACCESS•  Resources•  Beliefsystems•  Drugavailability•  HealthcarefaciliQes•  SQgma•  Sideeffects•  Lifelongtherapy

Funding

•  AtthecurrentrateofinfecQontheprojectedcostsofdelivering

andmaintaining“universalARTaccess”

•  $42billionin2010•  $54billionby2015

BenefitsofanHIVcure

•  Returntonormalhealthandlifeexpectancywithoutdrugs

•  RemovethelifeQmeriskofonwardtransmissionofvirus

•  Removetheneedforlifelongtreatment‐costs,toxicity,sustainability

•  Removetheriskofothernon‐HIVrelatedcomplicaQons,e.g.Cardiovasculardisease,cancers

WhycantART‘cure’?

•  ARTworksatcontrollingviralreplicaQonreversingimmunedamagebutneedslifelongtreatmentwithadherencetolerabilityandpotenQallytheriskofdevelopmentofdrugresistanceaswellascostimplicaQons

•  Virusisrapidlyspreadaroundthebodyalmostassoonastransmissionoccurs,asmallproporQonofcellsvirusincorporates‘hides’insidecellsandstaysthereunnoQcedbytheimmunesystemanddrugsforthelifespanofthosecells

•  These‘silently’infectedcellsarecalledthevirusreservoirandARTcannotremovethesevirusinfectedcells

Barrierstocure

•  LatentlyinfectedT‐cells

•  ResidualviralreplicaQon

•  Anatomicalreservoirs

Latentlyinfectedcellsarerare

HIV

RN

A C

D4 count

50

Whatdoesan“undetectableviralload”mean?

Years on HAART 0 1

HIV DNA

1

Palmer et al., Proc Natl Acad Sci U S A. 2008;105:3879-84 Maldarelli et al., Plos Pathogens 2007; 3:484

Anatomicalreservoirs

HIVeradicaQon:cureorremission

Cure Remission

Eliminate all HIV-infected cells No disease progression with no ART

HIV RNA < 1 copy/ml HIV RNA < 50 copies/ml

Sterilising cure Functional cure

Isthereachanceoffindingacure?

•  OnemanhasbeencuredofHIVinfecQon•  Possiblyonebaby“Missisipi”

Sterilisingcure:TimothyBrown

Hutter et al., N Engl J Med, 2009; 360:692

Chemox3

An+fungal,an+‐bacterial

CCR5stemcelltransplant

Transplantrejec+on(GVHD)

Totalbodyirradia+on

Neardeathx2

Howdiditwork?

•  Wasitthestemcelltransplantalone?– 2recentreportsof“nodetectablevirus”followingallogeneictransplantaQonwithconQnuousART•  Henrichetal.,IAC2012

•  WasittheCCR5Δ32transplant?

•  WasitGVHD?

•  WasitEVERYTHING!

WhereiscurrentHIVcureresearch

•  TimothyBrownrepresentsa‘Paradigmshim’inHIVtherapeuQcsItISpossibletocureHIV

•  NewdrugsthatworkincompletelydifferentwaysareneededtoaddtoanQretroviraltherapy

•  UnderstandingthekeymechanismsofwhyARTaloneisnotenoughtocureandwhatwasthekeycontributorincuringTimothyBrownmovedthefieldsignificantly

•  InternaQonalresearchisnowfocusingonHIVcureasanewchallenge:sowhatarewedoingintheUK?

Whatothertreatmentsmayconfera‘cure’?

•  Newdrugsthattryto‘wakeup’theresQnglatentlyinfectedcells:

•  HDACinhibitors‐Vorinostat/Romedepsin

•  IL‐7,IVIG,anQ‐PD‐1•  VaccinaQonsacQvatetheimmunesystemtorecognisethelatentlyinfectedcells

•  Genetherapythatblocks/deletestheHIVgenefromthelatentlyinfectedcells

Maybearemissionisenough

•  AslongasthereisnodetectablevirusinthebloodeveniftherearesQllsomelatentlyinfectedcellsthismaybeenough...

•  Preventsriskoftransmission,reducestheriskofanyHIVrelatedorunrelateddisease

•  Natural‘eliteviralcontrollers’•  Canwe‘convert’peopleintofuncQonalremissionwithART+?

Reservoirreducedwithearlytreatment

Time on HAART (years)

Log

HIV

DN

A co

pies

/ m

illio

n ce

lls

Chronic infection (n=135)

Acute infection (n=22)

Hocqueloux et al., 16th CROI, Montreal, 2009; abstract #515; Hocqueloux et al., AIDS 2010; 24:1598

FuncQonalcure:postARTcontrollers

Hocquelouxetal.,AIDS2010;Salgadoetal.,Retrovirology2011;8:97;Saez‐Cirionetal(unpublished)

VISCONTIcohort;n=12,treatedinacuteinfecQon;medianQmessincetreatmentinterrupQon72months

Year 01 02 03 04 05 06 07 08 09 10

CD

4+ T

cel

ls/m

m3

0

500

1000

1500

2000

RN

A co

pies

/ml

10 0

10 1

10 2

10 3

10 4

10 5

10 6

10 7

10 8

10 9 VisORA02

Summary

•  ForthefirstQmethepossibilityofHIVcurehasarealchance

•  ItwillprobablyrequireacombinaQonofintervenQonsandwillalwaysinvolveARTforatleastaperiodofQme

•  WeneedtoinvolvecommuniQesinfectedandaffectedbytheHIVepidemictodrivetherightethicalscienQficresearchwithrealisQcandopenopportuniQes

•  Therearemanydifferentapproachesthatlookencouragingbutallwillrequirealotmoreinvestmentofresources,energyscienQficdiscoveryandpaQence

CHERUBCollabora+ononHIVEradica+onResearchinthe

UKAUKHIVeradicaQontrialandresearchnetwork

Thanks

•  UKCHERUBcollaboraQon•  JohnFrater,JulieFox,MikeMalim,JohnCason,SabineKinloch,MarQnFisher,MargaretJohnson,JaneAnderson,JonathanWeber,AndrewLever,MarkWills,DeenanPillay,RaviGupta

•  UKNIHRBRC•  UKCAB,nam,ibase•  BHIVA