PopPopulation effect of Universal ulation effect of Universal

HIV testing and immediate HIV testing and immediate AART RT

therapy to therapy to RReduce HIV educe HIV

TTransmission ransmission -- PopARTPopARTTTransmission ransmission -- PopARTPopART

The research questionsThe research questions

The acceptability, feasibility, The acceptability, feasibility, The acceptability, feasibility, The acceptability, feasibility, effectiveness, costs safety and adverse effectiveness, costs safety and adverse effects of UTT have not been effects of UTT have not been establishedestablished

UTT interventions should only be UTT interventions should only be implemented after careful evaluation of implemented after careful evaluation of these parametersthese parameters

Testing the “universal testing” Testing the “universal testing”

conceptconcept

Can “Universal” testing be delivered whilst Can “Universal” testing be delivered whilst remaining thoughtful of human rights issues, remaining thoughtful of human rights issues, community consent and operational feasibility? community consent and operational feasibility?

What is the “best” way to deliver universal testing?What is the “best” way to deliver universal testing?What is the “best” way to deliver universal testing?What is the “best” way to deliver universal testing?

What should be the frequency of HIV testing?What should be the frequency of HIV testing?

What is the proportion of a population that need to What is the proportion of a population that need to and will accept HIV testing?and will accept HIV testing?

What resources will be required over and above What resources will be required over and above current standard practises to deliver this?current standard practises to deliver this?

What level of uptake of testing do we need to What level of uptake of testing do we need to achieve in order to impact the population effect of achieve in order to impact the population effect of the UTT conceptthe UTT concept

Some of the problems in HIV Some of the problems in HIV

testingtesting

The lack of a cross sectional incidence test The lack of a cross sectional incidence test makes it hard to know who has recently become makes it hard to know who has recently become infectedinfected

The frequency of HIV testing means PHI is The frequency of HIV testing means PHI is The frequency of HIV testing means PHI is The frequency of HIV testing means PHI is missed if annualmissed if annual

The marginalised and vulnerable “hard to reach” The marginalised and vulnerable “hard to reach” groups may never test but maybe the source of groups may never test but maybe the source of significant transmissions (e.g. IVDU, CSW, significant transmissions (e.g. IVDU, CSW, MSM, bisexual)MSM, bisexual)

Sexual behaviour within the population will Sexual behaviour within the population will impact the transmission probabilitiesimpact the transmission probabilities

Stage of infection

2

3

Infectiousness

Acute 31%

Asympt. 42%

AIDS 27%

Random mixing

(high risk

subpopulation)

Hollingsworth, Anderson & Fraser, J Infect Dis 2008

Abu’Raddad et al AIDS 2008, Pinkerton AIDS & Behavior 2008

0

1

0 2 4 6 8 10

Infectiousness

Years since infectionAcute 9%

Asympt. 71%

AIDS 20%

Serial monogamy

Concurrent

partnerships??

The concept of immediate The concept of immediate

ART for all HIV+veART for all HIV+ve

Do we really understand all the Do we really understand all the

issues of early ART?issues of early ART?

ProsProsEarlier treatment maybe beneficial to Earlier treatment maybe beneficial to

the individual the individual

Reduces the rates of TB (rate of TB Reduces the rates of TB (rate of TB

increases by 0.42 cases/100PYs per increases by 0.42 cases/100PYs per

ConsConsLack of data on longLack of data on long--term risk of drug term risk of drug

resistanceresistance

Lack of data on risk of toxicity vs Lack of data on risk of toxicity vs

clinical benefit of longer ART exposure clinical benefit of longer ART exposure 100 fall in CD4 count Lawn et al CROI 100 fall in CD4 count Lawn et al CROI

2009)2009)

Automatically takes care of PMTC Automatically takes care of PMTC

programs as all HIV+ve women are on programs as all HIV+ve women are on

ARTART

Reduces sexual transmission in Reduces sexual transmission in

monogamous HIV serodiscordant monogamous HIV serodiscordant

relationships (Donnell from 2.24 to relationships (Donnell from 2.24 to

0.37 risk of transmission CROI 2010 0.37 risk of transmission CROI 2010

#136) HPTN 052#136) HPTN 052

clinical benefit of longer ART exposure clinical benefit of longer ART exposure

(START trial)(START trial)

Acceptability within communities Acceptability within communities

where HIV status remains stigmatisingwhere HIV status remains stigmatising

Feasibility of operationally delivering Feasibility of operationally delivering

ART to almost all the HIV+ve ART to almost all the HIV+ve

population (San Francisco MSM population (San Francisco MSM

achieved >90% ART coverage to achieved >90% ART coverage to

confer a reduction in incidence) Is this confer a reduction in incidence) Is this

best use of resourcesbest use of resources

How to deliver “immediate ART for all How to deliver “immediate ART for all HIV+veHIV+ve” ”

How long after diagnosis should “immediate” ART be offeredHow long after diagnosis should “immediate” ART be offered

How can this be delivered given that many resource limited settings How can this be delivered given that many resource limited settings How can this be delivered given that many resource limited settings How can this be delivered given that many resource limited settings are struggling to deliver WHO guidelines (CD4<200)? How will this are struggling to deliver WHO guidelines (CD4<200)? How will this impact the communities where participants in a study group maybe impact the communities where participants in a study group maybe offered ART before others who are sick?offered ART before others who are sick?

Practically how can immediate ART be easily and directly linked to Practically how can immediate ART be easily and directly linked to testing testing

How sustainable is such a concept given pressure on resources How sustainable is such a concept given pressure on resources especially after a trial has finished?especially after a trial has finished?

What ART regimen can be offeredWhat ART regimen can be offered-- low toxicity ease of regimen, low toxicity ease of regimen, safety high resistance threshold in line with country treatment safety high resistance threshold in line with country treatment guidelines.guidelines.

Potential trial designsPotential trial designs

‘ecological’‘ecological’ try it and see what happenstry it and see what happens-- MSM MSM San Francisco, IVDU British Columbia, USA San Francisco, IVDU British Columbia, USA TnTTnTprotocol protocol protocol protocol

Randomised controlled trialsRandomised controlled trials: randomise to UTT : randomise to UTT or standard care at an individual levels and or standard care at an individual levels and monitor HIV incidence within a populationmonitor HIV incidence within a population

Community randomised trialsCommunity randomised trials: randomise : randomise identified matched communities to either UTT identified matched communities to either UTT protocol or standard care and test HIV incidence protocol or standard care and test HIV incidence within each communitieswithin each communities--TasPTasP and and PopARTPopART

PopARTPopART

An initial feasibility and An initial feasibility and

acceptability pilot studyacceptability pilot study

PopART MembershipPopART Membership

United KingdomUnited KingdomImperial College LondonImperial College London

–– Geoffrey GarnettGeoffrey Garnett

–– Sarah FidlerSarah Fidler

–– Christophe FraserChristophe Fraser

Africa: PIs fromAfrica: PIs from

UgandaUganda--Heiner Grosskurt, Heiner Grosskurt, Anatoli Kamali, Paula Munderi, Anatoli Kamali, Paula Munderi, –– Christophe FraserChristophe Fraser

–– Becky BaggaleyBecky Baggaley

–– Jonathan WeberJonathan Weber

–– Institute of Global Health Peter PiotInstitute of Global Health Peter Piot

MRC CTUMRC CTU

–– Adbel BabikerAdbel Babiker

–– Sheena McCormackSheena McCormack

LSHTMLSHTM

–– Richard HayesRichard Hayes

–– David RossDavid Ross

UK AllianceUK Alliance

–– Ade FakoyaAde Fakoya

UCLUCL

–– Andrew PhillipsAndrew Phillips

Anatoli Kamali, Paula Munderi, Anatoli Kamali, Paula Munderi, Janet Seeley, Rosalind ParkesJanet Seeley, Rosalind Parkes

ZambiaZambia--Helen Ayles, Ginny Helen Ayles, Ginny BondBond

MalawiMalawi--Liz CorbettLiz Corbett

International International collaboratorscollaboratorsGlobal Fund AIDS TB & Malaria Global Fund AIDS TB & Malaria (GFATM), UNAIDS, WHO(GFATM), UNAIDS, WHO

PopART scope of proposed workPopART scope of proposed work

an initial feasibility and acceptability an initial feasibility and acceptability

studystudy

Mathematical and cost effective modellingMathematical and cost effective modelling

Epidemiological, social science research Epidemiological, social science research Epidemiological, social science research Epidemiological, social science research

and data collationand data collation

Community engagement and acceptabilityCommunity engagement and acceptability

Test the uptake of UTT Test the uptake of UTT

Inform the capability and design and need Inform the capability and design and need

for a CRT to test the hypothesisfor a CRT to test the hypothesis

GeneralisabilityGeneralisability

How do we select representative cluster How do we select representative cluster

populations?populations?

Country/site specific work plans will need Country/site specific work plans will need

to identify gaps between current practice to identify gaps between current practice

and the and the PopARTPopART UTT approach and UTT approach and

determine strategies to bridge these gaps.determine strategies to bridge these gaps.

PopART African partnersPopART African partnersUganda, ZambiaUganda, Zambia

In order to conduct a robust and valuable In order to conduct a robust and valuable

study more than one site is required to study more than one site is required to

determine the generalisability policy determine the generalisability policy determine the generalisability policy determine the generalisability policy

relevance of the results and to provide a relevance of the results and to provide a

sufficient number of large geographical sufficient number of large geographical

clusters for the proposed CRT. clusters for the proposed CRT.

Resource constraints may threaten thisResource constraints may threaten this

1. Mathematical modelling1. Mathematical modelling

What % HIV+ threshold of detection is required to demonstrate an What % HIV+ threshold of detection is required to demonstrate an effecteffect

What % uptake of VCT and subsequent ART uptake is required to What % uptake of VCT and subsequent ART uptake is required to What % uptake of VCT and subsequent ART uptake is required to What % uptake of VCT and subsequent ART uptake is required to demonstrate an effectdemonstrate an effect

With what tools and how frequently should HIVWith what tools and how frequently should HIV--testing be performedtesting be performed

What is the risk of viral drug resistance and toxicityWhat is the risk of viral drug resistance and toxicity

What are the most appropriate ART regimens and how will therapy What are the most appropriate ART regimens and how will therapy be monitored ref DARTbe monitored ref DART

What is the cost benefit analysisWhat is the cost benefit analysis

Set parameters for CRTSet parameters for CRT

2.2. EpidemiologyEpidemiology

Collate and validate current VCT, prevalence and Collate and validate current VCT, prevalence and incidence data ART provision, capacity, drug supply incidence data ART provision, capacity, drug supply chain, availability of skilled personnel, community chain, availability of skilled personnel, community chain, availability of skilled personnel, community chain, availability of skilled personnel, community commitment and acceptability of the planned commitment and acceptability of the planned intervention. intervention.

What is the best source of current data available to What is the best source of current data available to inform the model?inform the model?

What are the gaps that need to be collected from the What are the gaps that need to be collected from the pilot work to best direct the models?pilot work to best direct the models?

What are the resource requirements to deliver the What are the resource requirements to deliver the Universal test and treat approach and would this confer Universal test and treat approach and would this confer adverse effects on other health care provisionadverse effects on other health care provision

3. Acceptability3. Acceptability

Acceptability; Engage with country all levels of Acceptability; Engage with country all levels of stakeholdersstakeholders

National stakeholder and community engagement and National stakeholder and community engagement and acceptability of interventions acceptability of interventions National stakeholder and community engagement and National stakeholder and community engagement and acceptability of interventions acceptability of interventions –– Selected focus groupsSelected focus groups

–– Community buyCommunity buy--inin

–– collaborating research institutions collaborating research institutions

–– stakeholders including community leaders and advocacy groups.stakeholders including community leaders and advocacy groups.

Design CRT protocol Design CRT protocol

Define potential future cluster sites & select appropriate Define potential future cluster sites & select appropriate committed communitiescommitted communities

4. Intervention population test 4. Intervention population test

delivery and acceptability of delivery and acceptability of

immediate ARTimmediate ART

Within populations enrolled into the feasibility Within populations enrolled into the feasibility study every individual identified as HIV+ve will study every individual identified as HIV+ve will be offered immediate ARTbe offered immediate ART-- probably Atripla or probably Atripla or be offered immediate ARTbe offered immediate ART-- probably Atripla or probably Atripla or generic generic

Funding for the ART will be sought from Funding for the ART will be sought from ?GFATM country level or Pharma,?GFATM country level or Pharma,

Ministry of Health collaboration & all level Ministry of Health collaboration & all level stakeholder support is critical as longstakeholder support is critical as long--term term continued provision of ART after the initial study continued provision of ART after the initial study period must be guaranteed prior to starting the period must be guaranteed prior to starting the study.study.

Universal testing strategy;Universal testing strategy;

A joint community and houseA joint community and house--toto--

house protocolhouse protocol

Link with other agencies to enhance Link with other agencies to enhance

uptake and bring different funding bodies uptake and bring different funding bodies

together; e.g. TB prevention, provision of together; e.g. TB prevention, provision of together; e.g. TB prevention, provision of together; e.g. TB prevention, provision of

water filters, malaria net provision, water filters, malaria net provision,

contraception then follow up withcontraception then follow up with

HouseHouse--toto--house testing with community house testing with community

support has delivered >90% uptake of HIV support has delivered >90% uptake of HIV

testing in Ugandatesting in Uganda

Social science researchSocial science research

Will increased but only annual HIV testing Will increased but only annual HIV testing affect sexual behaviour and be counter affect sexual behaviour and be counter effective?effective?effective?effective?

What proportion of transmissions occur What proportion of transmissions occur from individuals with recent infectionfrom individuals with recent infection--that that would be missed with annual testing would be missed with annual testing strategies ?strategies ?--probably up to 50% in MSM probably up to 50% in MSM and focused epidemics may be less in and focused epidemics may be less in heterosexual more stable populationsheterosexual more stable populations

Requirements for a future CRTRequirements for a future CRT-- will will

we need a CRT?we need a CRT?

Successful completion of the pilot study in two countries showing no Successful completion of the pilot study in two countries showing no clear evidence of harm e.g. development of drug toxicity and clear evidence of harm e.g. development of drug toxicity and resistanceresistance

intervention was feasible to implement from operational and intervention was feasible to implement from operational and economic perspectives economic perspectives

A provisional agreement at a national level supported by the GFATM A provisional agreement at a national level supported by the GFATM that, if funding is provided for a CRT, there will be commitment to that, if funding is provided for a CRT, there will be commitment to provision of continuing treatment after the end of the trial. provision of continuing treatment after the end of the trial.

Evidence to support the costEvidence to support the cost--effectiveness of the intervention effectiveness of the intervention strategy in the longstrategy in the long--term. term.

Other studies that will inform many Other studies that will inform many

of the current issuesof the current issues

HPTN 052HPTN 052

MP3 MalawiMP3 MalawiMP3 MalawiMP3 Malawi

TnT (USA)TnT (USA)

TAsPTAsP

Partner study (European)Partner study (European)

START trial START trial

Ecological studiesEcological studies-- San Francisco, British San Francisco, British ColumbiaColumbia