Choosing the Primary Endpoint for HIV prevention Trials; The example of HPTN071/PopART

NATIONAL INSTITUTES OF HEALTH:National Institute of Allergy and Infectious Diseases

National Institute of Mental HealthNational Institute on Drug Abuse

Choosing the Primary Endpoint for HIV prevention Trials; The example

of HPTN071/PopART

Helen Ayles, Sian Floyd, Ab Schaap, Anne Cori, Mike Pickles, Christophe Fraser, Deborah Donnell, Nulda Beyers, Sarah Fidler, Richard Hayes and

the HPTN 071 (PopART) Team.

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Population effect of universal testing and immediate ART therapy to Reduce HIV Transmission

PopART:

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Universal voluntary HIV testing

with appropriate combination

prevention offered to all those

testing HIV negative - in addition

to immediate ART for all those

testing HIV positive - will have a

substantial impact on HIV

incidence at population level

Hypothesis

Lancet 2009 373: 48-57 4

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• Not known whether a UTT intervention can be delivered with high uptake and acceptability

• Many uncertainties in model parameters

• Population-level impact of intervention package is not known

• Potential adverse effects such as sexual risk disinhibition, HIV-related stigma, overload of health services, toxicity, and drug resistance

• A rigorously designed trial can measure the costs and benefits of this strategy and provide reliable evidence on cost-effectiveness for health policy makers

Why is a Trial Needed?

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• This trial was designed to ask– “Does a strategy of combination HIV prevention

including universal HIV testing and treatment reduce HIV transmission (incidence) at community level?”

• Primary outcome was clearly incidence but how to measure?

Choosing the Primary Endpoint

• HIV incidence will be estimated by assessing HIV seroconversion in a longitudinal cohort (the PC)

Advantages• Gold standard approach for HIV incidence estimation• Uses routine HIV test methods• Provides interim and cumulative incidence estimates• Cohort allows for measurement of other indicators such as sexual behaviour, HSV2Disadvantages• Requires longitudinal cohort follow-up

– Impacted by loss-to-follow up, including differential loss to follow-up (e.g., of those at higher risk of HIV acquisition)

– Hawthorne effect– Complex sampling is needed to ensure that the cohort reflects the population as a whole

• HIV incidence prior to enrollment may also be estimated using a multi-assay algorithm (cross-sectional incidence estimate)

• This approach was recently used for primary endpoint determination in a large, community-randomized clinical trial (NIMH Project Accept [HPTN 043])

Coates et al., Lancet Global Health 2014; 2:e267-277)

• Provides an estimate of HIV incidence in the months prior to study enrollment

Measuring HIV Incidence

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Design issues• What should the combination prevention package contain?

– HCT- universal uptake– Linkage to care and provision of ART– Sexual risk reduction– VMMC– PMTCT– STI– TB

• What scenarios would be useful to policy makers?– Universal test Vs Universal test and treat Vs current– Costs of each– Delivery under routine programmatic conditions as far as

possible

• What effectiveness is possible?

Health centre

VMMC facility

Universal testing: annual door-to-door HBT

Follow-up on referral Support for:

- Retention in care- Adherence to treatment

CHiPs: Community HIV-care ProvidersPMTCT: Prevention of Mother to Child TransmissionVMMC: Voluntary Medical Male CircumcisionTB: TuberculosisSTI: Sexually Transmitted Infections

Service promotion and referral for- HIV care for HIV +ve

including PMTCT- VMMC- TB - STI

Universal treatment for HIV +ve

irrespective of CD4 count

Facilitated by CHiPs

PopART Intervention Package

ART initiation according to current national guidelines*

PopART intervention

except

3 arm cluster-randomised trial with 21 communities (N ≈ 1.2million total population)

Full PopARTintervention

including

immediate ART irrespective of CD4

count

Standard of care at current service provision levels

including

ART initiation according to current national guidelines*

*originally CD4-count <350 cells/mm3

Arm A Arm B Arm C

Final Trial Design

• Communities matched into 7 triplets on geographical area and HIV prevalence• Average of ~50,000 in each cluster (~ 50% adults)• Incidence measured in Population Cohort:

2,500 adults in each cluster, followed up after 1, 2 and 3 years

9 communities in South Africa

12 communities in Zambia

21 communities in 3 arms

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Calculating sample size: The role of mathematical modelling

• Deterministic compartmental model of individuals aged 15+

• Heterosexual mixing

• Three risk groups

Cori et al. PLoS One, 2014

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Model calibration:- to national HIV prevalence estimates from UNAIDS- and ART coverage data from Zamstar

Best fit, national guidelines CD4<350, central target

Za

mb

iaS

out

h A

fric

a

What is the influence of process parameters?

treatment drop-out/failure

• Relative reduction in 3-year HIV incidence in arms A and B

• Linear model

efficacy of ART in blocking transmission

uptake of testing, ART and circumcision

% sex acts with partners from other communities

Effect of counselling on infectivity

Delays in linkage to care

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Arm A

Arm B

Zambia



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Arm A

Arm B

Zambia

R2>0.98

Contributions to variability in outcome




1

2

12

12


15

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Summary : projected reduction in 3-year cumulative HIV incidence

Zambia South Africa

Relative reduction

Arm A

Relative reduction

Arm B

Mean annual incidence

Arm C

Relative reduction

Arm A

Relative reduction

Arm B

Mean annual incidence

Arm C

Best fit, central target 61% 25% 1.85% 62% 26% 1.36%

95% variability due to uptake level(pessimistic-optimistic

targets)

42-75% 15-33% 1.85% 44-75% 16-33% 1.36%

• Power calculations, best fit, central target (incidence 1.5% k 0.2):– A versus C: 100%– B versus C: 48%– A versus B: 96%

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Impact of the new WHO guidelines:scenarios 1- 4 ; projected reduction in 3-year cumulative HIV incidence

Scenario 1 Scenario 2 Scenario 3 Scenario 4

Late adoption

Late adoption

Early adoption

Early adoption

Small eligibility

Large eligibility

Small eligibility

Large eligibility

• 2 hypotheses regarding starting date: – Early adoption: 1st January 2014– Late adoption: 1st January 2015

• 2 hypotheses regarding population affected by new guidelines: – Large eligibility: 90% testing and linkage to care in ANC & 30% HIV+ individuals with

CD4>500 in a serodiscordant couple or co-infected with TB or Hep B– Small eligibility: 40% testing and linkage to care in ANC & 5% HIV+ individuals with

CD4>500 in a serodiscordant couple or co-infected with TB or Hep B

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Impact of the new WHO guidelines:scenarios 1- 4 ; projected reduction in 3-year cumulative HIV incidence

Zambia South Africa

Rel. red. Arm A

Rel. red.Arm B

Mean annual incid. Arm C

Rel. red. Arm A

Rel. red.Arm B

Mean annual incid. Arm C

Best fit, central target

61%59%58%58%56%*

25%31%32%35%37%

1.85%1.75%1.68%1.67%1.53%

62%61%60%60%58%*

26%32%33%37%39%

1.36%1.32%1.28%1.28%1.20%

95% variability due to intervention

uptake level(pessimistic-optimistic targets)

42-75% 15-33% 1.85% 44-75% 16-33% 1.36%

* Also validated by independent calculation based on Eaton et al., Lancet Global Health, 2014

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• Using sample size of 2500 per cluster, incidence over 3 years,

Study power under new scenarios

HIV incidence

rate/ 100py(control

arm)

Between-cluster

coefficient of variation

(k)

Reduction arm A

Reduction arm B Arm A

vs Arm C

Arm B Vs Arm C

Arm A Vs Arm B

1.0 0.2 55% 30% 99% 60% 71%

1.0 0.2 60% 35% 100% 71% 77%

1.5 0.2 55% 30% 100% 65% 78%

1.5 0.2 60% 35% 100% 80% 83%

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Conclusions

• HPTN071 will use a cohort measure of HIV incidence to assess the effectiveness of a package of combination HIV prevention including a “universal test and treat” approach

• Adoption of new consolidated WHO guidelines in Zambia and South Africa should only moderately affect ability to detect differences between arms in the HPTN-071 (PopART) trial

• Main trial outcome mostly depends on– Community-level changes in behaviours – Efficacy of ART in blocking transmission (adherence)– Uptake of HIV testing, treatment and circumcision

• All of these process measures are being actively measured during the trial

ACKNOWLEDGEMENTS

• Sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) under Cooperative Agreements # UM1 AI068619, UM1-AI068617, and UM1-AI068613

• Funded by:

– The U.S. President's Emergency Plan for AIDS Relief (PEPFAR)

– The International Initiative for Impact Evaluation (3ie) with support from the Bill & Melinda Gates Foundation

– NIAID, the National Institute of Mental Health (NIMH), and the National Institute on Drug Abuse (NIDA) all part of the U.S. National Institutes of Health (NIH)

The HPTN 071 Study Team, led by:Dr. Richard Hayes

Dr. Sarah FidlerDr. Helen Ayles

Dr. Nulda Beyers

Implementing Partners:

Government Agencies:

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• All research participants and their families

• The 21 research communities and their religious, traditional, secular and civil leadership structures

• Volunteers in the community advisory board structures

With thanks to:

Choosing the Primary Endpoint for HIV prevention Trials; The example of HPTN071/PopART

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