Treatment as prevention: a new paradigm for HIV control?

1. Treatment as prevention: a new paradigm for HIV control? Richard Hayes

2. Treatment as prevention • Background and rationale • Design of PopART/HPTN071 trial • Other planned trials

3. ART for prevention: background • HIV incidence continues to be unacceptably high in many countries in Africa • Lack of proven effective HIV prevention strategies • Unless incidence can be reduced dramatically it will become increasingly difficult over time to sustain effective ART services

4. Lancet 2009 373: 48-57

5. ART for prevention: background • HIV incidence continues to be unacceptably high in many countries in Africa • Lack of proven effective HIV prevention strategies • Unless incidence can be reduced dramatically it will become increasingly difficult over time to sustain effective ART services • Risk of HIV transmission closely correlated with HIV viral load and ART can be used to reduce HIV viral load and hence infectivity

6. Rakai Study of viral load and HIV transmission Quinn et al, NEJM 2000

7. Evidence from HPTN 052 • 1763 HIV-discordant couples in 9 countries, CD4=250-550 • Randomized to immediate or deferred treatment • Stopped for efficacy • 39 HIV-ve partners were infected of which 29 were linked virologically to the infected partner • Of these 29 only 1 was in the immediate treatment group • HR = 0.04 (95% CI: 0.01–0.27) • Also significant reduction in morbidity endpoints in treated individuals – HR for serious clinical endpoints = 0.59 (95% CI: 0.40-0.88)

8. ART for prevention: background • HIV incidence continues to be unacceptably high in many countries in Africa • Lack of proven effective HIV prevention strategies • Unless incidence can be reduced dramatically it will become increasingly difficult over time to sustain effective ART services • Risk of HIV transmission closely correlated with HIV viral load and ART can be used to reduce HIV viral load and hence infectivity • Current guidelines limit ART to those with late-stage HIV infection (CD4<200 or CD4<350) but most transmission occurs before that

10. Universal test and treat intervention • Promote universal HIV voluntary counselling and testing at regular intervals • All those diagnosed HIV positive are started on ART immediately • Model shows immediate increase in numbers needing treatment but in medium-term, HIV incidence and prevalence are reduced dramatically • In long-term, numbers needing ART are reduced.

11. Why is a trial needed? • Not known whether a UTT intervention can be delivered with high uptake and acceptability • Many uncertainties in model parameters • Population-level impact of (feasible) intervention package is not known • Many potential adverse effects, such as toxicity, drug resistance, sexual risk disinhibition, HIV-related stigma, overload of health services • A rigorously designed trial can measure the costs and benefits of this strategy and provide reliable evidence on cost-effectiveness for health policy makers

12. HPTN 071 = PopART Population effect of universal testing and immediate ART therapy to Reduce HIV Transmission

13. The PopART intervention package • Universal voluntary HIV testing delivered through a house-to-house campaign • Male circumcision offered to men who test HIV-negative • Immediate ART offered to all who test HIV-positive • Counselling and condom provision • Strengthening of PMTCT services • Syndromic STI treatment at clinic • CHiPs team (Community HIV Providers) to deliver testing, counselling, linkage to care and treatment support

14. Additional benefits of intervention – individual and public health • Reduction of morbidity and mortality in those receiving ART through earlier onset of treatment • Simplification of ART delivery and monitoring • Reduction of adverse effects of treatment • Reduction of clinic burden of TB and other illnesses • (Potential) elimination of mother to child HIV transmission • (Eventual) cost savings • Normalisation of HIV and reduction in HIV-related stigma • Reduces need for specially targeted interventions

15. Design of trial • 24 clusters (15 in Zambia + 9 in S Africa) • Cluster = community served by a health facility • Variable population size but averages 50-60k • Clusters matched into triplets by HIV prevalence: 5 triplets in Zambia, 3 in S Africa • Clusters randomly allocated to 3 study arms within each matched triplet • Restricted randomisation used to ensure balance on ART uptake, population size and HIV prevalence

16. Location of study clusters

17. Study arms • Arm A (8 clusters): Full PopART intervention including immediate ART irrespective of CD4 count • Arm B (8 clusters): Full PopART intervention except that ART is initiated according to current national guidelines (CD4 < 350 or WHO stage 3/4) • Arm C (8 clusters): Standard of care

18. Evaluation surveys • Population cohort (All 3 arms) • 2,500 adults aged 18-44 sampled randomly from general population of each cluster (1 adult per household) • Total size of cohort = 2,500 x 24 = 60,000 • Followed up after 1 year and 2 years of intervention • Population cross-sectional survey (All 3 arms) • 500 adults aged 18-44 sampled randomly from general population of each cluster (all adults in selected households) • Total size of survey = 500 x 24 = 12,000 • At final follow-up after 2 years of intervention

19. Evaluation surveys • Clinic cohort (All 3 arms) • Sample of 300 HIV+ve patients presenting at clinic to register for HIV treatment and care • Total size of cohort = 300 x 24 = 7,200 • Followed up for 2 years

20. Primary outcome • Population cohort • HIV incidence over 2 years • Will also look at impact during first year and second year of follow-up

21. Secondary outcomes • Population cohort • HSV-2 incidence (marker of risk behaviour) • Population cohort and Population cross-sectional survey • Sexual risk behaviour and HIV-related stigma • Community HIV viral load, CD4 count, drug resistance • Uptake of services • HIV-free infant survival • TB prevalence

22. Secondary outcomes • Clinic cohort • HIV disease progression, CD4 count, morbid events • ART adherence and viral suppression • Drug resistance • Clinic and CHiPs records • Uptake of services • TB case notification, clinic burden by cause

23. Model projections of impact

24. Targets and projected impact

25. Sample size for Arm A or B vs C

26. Funding of PopART/HPTN071 • OGAC (PEPFAR) • Bill & Melinda Gates Foundation • NIH • PopART is one of 3 trials of combination HIV prevention supported by OGAC • 2 other trials in Botswana (Harvard) and Tanzania (JHU)

27. Other planned trials (1) • Iringa, Tanzania (2 arms) • Arm A: Expanded testing/linkage to care, ART at CD4<350, IEC, male circumcision, conditional cash transfers, targeted outreach • Arm B: Standard of care • 24 clusters (12 vs 12) • Cohort of 500/cluster, total 12,000, 24m follow-up • Botswana (2 arms) • Arm A: Expanded testing/linkage to care, ART at CD4<350 OR VL>10,000, male circumcision • Arm B: Standard of care • 20 clusters (10 vs 10) • Cohort of 500/cluster, total 10,000, 36-48m follow-up

28. Other planned trials (2) • KwaZulu Natal, S Africa (2 arms) – TasP trial • Arm A: Expanded testing, male circumcision, immediate ART, IEC, STI treatment etc. • Arm B: As above but ART at CD4<350 • 32 clusters (16 vs 16) • 1,250/cluster, total 40,000, 24m follow-up (total population) • Funding currently available for initial feasibility study in 4 of the 32 clusters

29. The HPTN 071 team LSHTM Zambart Richard Hayes Helen Ayles Debby Watson-Jones Virginia Bond KalpanaSabapathy Nathaniel Chisinga Sian Floyd AbSchaap Lucy Bradshaw Imperial College Desmond Tutu TB Centre Sarah FidlerNuldaBeyers Christophe Fraser Peter Bock Peter Smith Lyn Horne

30. The HPTN 071 research team HPTN/FHI360 HPTN Network Lab StenVermund Sue Eshleman Ayana Moore Estelle Piwowar-Manning Sam Griffith Rhonda White DAIDSSCHARP David Burns Deborah Donnell Peter Kim Lynda Emel