Richard hayes London school of hygiene & Tropical Medicine Adapting global and national guidelines in a large implementation science study HPTN 071 (PopART) Richard hayes London school of hygiene & Tropical Medicine

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)

Outline of presentation Objectives of HPTN 071 (PopART) trial Overview of trial design Responding to changing global and national guidelines Transition to universal treatment Continuing importance of study questions

Objectives of HPTN 071 (PopART) trial Measure the effectiveness and cost-effectiveness of a combination prevention package Including universal testing and treatment (UTT) and other proven HIV prevention methods Generalised epidemic in Southern Africa – urban communities Cluster-randomised trial Impact on HIV incidence at population level Implementation science: can a UTT intervention be implemented on a wide scale with high coverage?

~ 2,000 random sample from each community : HIV incidence at 36 months Trial Design Total Population ~ 1M ~ 2,000 random sample from each community : Population Cohort N ~ 42,000 12 in Zambia 9 in S. Africa Primary outcome: HIV incidence at 36 months

~ 2,000 random sample from each community : HIV incidence at 36 months Trial Design Total Population ~ 1M ~ 2,000 random sample from each community : Population Cohort N ~ 42,000 12 in Zambia 9 in S. Africa Primary outcome: HIV incidence at 36 months PopART intervention package Annual rounds of Home Based Voluntary HIV Testing by Community HIV-care Providers (CHiPs) Health promotion, Active Referral and/or Retention in Care support by CHiPs for the following: Voluntary Medical Male Circumcision (VMMC) for HIV negative men Prevention of Mother to Child Transmission (PMCT) for HIV positive women HIV treatment and care for all HIV positive individuals Promotion of sexual health and TB services Condom provision ART irrespective of CD4-count or immune-status provided at the local health centre in Arm A

Changing guidelines for ART initiation: provisions of study protocol Arm A: Immediate offer of ART irrespective of CD4 count Arms B and C: ART according to current national treatment guidelines Consent: Individuals in Arm A who are offered ART initiation outside current national treatment guidelines are asked for informed consent

Previous guideline changes

“ART should be initiated in everyone living with HIV at any CD4 cell count”

Trial Design 12 in Zambia 9 in S. Africa

Trial Design

Planning for expedited transition in Arms B and C V3.0 of protocol developed to allow for transition ahead of changes in local guidelines if necessary All required ethics approvals secured for V3.0 Transition implemented in April/May 2016 in Zambia – part of an MoH pilot preceding national roll-out – so consent no longer required Discussions in progress with DoH and other stakeholders in SA Study remains well-powered because projected impact limited without intensive community-based intervention

Study power – with and without guideline change Over 3 years Over years 2&3 Pessimistic Central Optimistic With change Effectiveness 36% 42% 48% 40% 47% 56% Incidence 1%, k=0.15 Study power 84% 94% 98% 82% 93% 99% Incidence 1.5%, k=0.2 79% 91% 97% 81% Without change 43% 49% 57% 95% 92% Assumes PC sample size of approximately 2,000 per community Arm A compared with Arm C

Is there still equipoise? Immediate start of ART: No longer clinical equipoise – clear evidence of benefit – reason for seeking expedited transition But Immediate ART ≠ Test-and-Treat Test (and retest) → Link → Start ART → Adherence/suppression We do not know If UTT can be delivered at population level with sustained high coverage The impact on HIV incidence at population-level The cost-effectiveness of this strategy This will be key evidence to inform measures to achieve the SDGs leading to long-term elimination of HIV

Key questions we are trying to answer Can a Universal Testing and Treatment (UTT) intervention be delivered on a large scale? What uptake and coverage can be achieved by such an intervention and can this be sustained over time? What is the impact of such an intervention on HIV incidence at population level and how does this build up over time? What is the cost-effectiveness of the intervention? Important to answer these questions in context of guidelines for ART initiation that will apply when study is completed!

The HPTN 071 Study Team, led by: PEPFAR Implementing Partners: Dr. Richard Hayes Dr. Sarah Fidler Dr. Helen Ayles Dr. Nulda Beyers Government Agencies: PEPFAR Implementing Partners:

With thanks to: 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