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

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

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

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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

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

Evidence from HPTN HIV-discordant couples in 9 countries, CD4= 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: )

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

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.

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

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

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

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

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

Location of study clusters

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

Evaluation surveys Population cohort (All 3 arms) 2,500 adults aged 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 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

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

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

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

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

Model projections of impact

Targets and projected impact

Sample size for Arm A or B vs C

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)

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 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

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< 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

The HPTN 071 team LSHTMZambart Richard HayesHelen Ayles Debby Watson-JonesVirginia Bond Kalpana SabapathyNathaniel Chisinga Sian FloydAb Schaap Lucy Bradshaw Imperial CollegeDesmond Tutu TB Centre Sarah FidlerNulda Beyers Christophe FraserPeter Bock Peter SmithLyn Horne

The HPTN 071 research team HPTN/FHI360HPTN Network Lab Sten VermundSue Eshleman Ayana MooreEstelle Piwowar-Manning Sam Griffith Rhonda White DAIDSSCHARP David BurnsDeborah Donnell Peter KimLynda Emel