1. Treatment as Prevention (TasP)
Dr Michael Brady
Medical Director, Terrence Higgins Trust
Consultant, HIV & Sexual Health

2. Reducing onward transmission: Viral suppression among key population groups living with HIV in the United Kingdom. 19th Annual Conference of the British HIV Association (BHIVA) April 2013, Valerie Delpech, Alison Brown, Stephano Conti, Venkata Polavarapu, Zing Yin

3. Effect size (95% CI) 96% (73; 99) 73% (49; 85) 63% (22; 83)
Study
Effect size (95% CI)
96% (73; 99)
Treatment for prevention
Tenofovir/Truvada for discordant couples
73% (49; 85)
Truvada for heterosexuals
63% (22; 83)
0% %
Medical male circumcision
54% (38; 66)
Truvada for MSMs
44% (15; 63)
39% (6; 60)
Tenofovir vaginal (coital)
Prime boost Vaccine
31% (1; 51)
Truvada for women
0% (-69; 41)
MMC provides benchmark for robust evidence
Prime boost cannot exclude chance, but makes biological sense to combine products aimed at 1) cellular and 2) humoral immune responses
Discordant couples highly motivated to adhere; most variable effectiveness across trials is in women
Treatment of positive partners most impressive in terms of strength of response, but note that a third of infections were acquired outside the main partnership (similar to other trials in these populations)
Truvada for women
0% (-50; 30)
Tenofovir gel (daily)
for women
15% (-20; 40)
Efficacy

4. Primary Transmission Endpoint Primary Clinical Endpoint
HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Immediate ART CD
Delayed ART
CD4 <250
Randomization
HPTN 052 enrolled serodiscordant couples and the infected participant required CD4 counts between 350 and Infected participants were either offered immediate combination ART, or ART was delayed until CD4 fell between 20 and 250, but as close to 250 as possible. Two points to be made: when the study was designed WHO guidelines recommended that ART be initiated before CD4 fell below Second, discordant couples are special and even a little unusual, because HIV transmission has not occurred. The primary endpoint of this study was measurement of linke transmission of HIV. We also messured clinical events and death as a stand alone endpoint, and as part of a composite endpoint that considered prevention and treatment benefits concomitantly. The composite endpoint served as a pre-arranged intervention boundary for the DSMB.
Primary Transmission Endpoint
Virologically-linked transmission events
Primary Clinical Endpoint
WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death 4

5. HPTN 052 Enrollment Immediate Arm 886 Couples Delayed Arm 877 Couples
10,838 Individuals Screened
Major reasons for exclusion:
3058 HIV+ but CD4 count out of range
2565 HIV- but HIV+ partner ineligible
308 Seroconcordant couples
155 Ineligible due to sexual history
1763 Couples
(3526 Individuals)
Randomized
We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men (WE NEED TO DELETE SOME DETAIL!!)
Immediate Arm
886 Couples
Delayed Arm
877 Couples 5

6. (Total Enrollment: 1763 couples)
HPTN 052 Enrollment
(Total Enrollment: 1763 couples)
U.S.
Brazil
South Africa
Botswana
Kenya
Thailand
India
Americas
278
Africa
954
Asia
531
Zimbabwe
Malawi
WE NEED A MAP WITH n by site OR A LIST OF SITE and N?? 6

7. Transmission HPTN 052: HIV-1 Transmission 96% reduction in HIV
Total HIV-1 Transmission Events: 39
96% reduction in HIV
Transmission
Linked Transmissions: 28
Unlinked or TBD Transmissions: 11
We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men (WE NEED TO DELETE SOME DETAIL!!)
18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3
23/28 (82%) transmissions in sub-Saharan Africa
18/28 (64%) transmissions from female to male partners
Immediate Arm: 1
Delayed Arm: 27
p < 0.001 7

8. One Transmission Event on ART Index begins ART AZT/3TC/EFV
Index VL<400
Partner HIV+ (WB)
Enrollment
Screening
Days
-14 1 28 85
How could a transmission event occur in the faceof ART. We examine the virus tramsmitted for information. The coules was screeed on Sept and the partner was negative, On Sept 29 the patient started ART and VL was suppressed by??? The partner had acquired as single viru from the index case by DEc23. Examination of the viris suggests it was acquied more than84 days earlier. The screening visit was exactly 84 days earlier. We believe transmissio occurred befire ART could uppress genital tract HIV.
Partner VL < 400
Index CD4 = 482
Index VL = 87,202
Single Genome Analysis: 1-2 viruses transmitted
Analysis of Transmission: >50 days earlier (84 – 190 days) 8

9. HIV Treatment Guidelines
Recommended CD4 at start of therapy
WHO (2013)
< 500
BHIVA (2013)
< 350
Respect decision if patient wants to start to reduce transmission
DHHS - USA (2012)
All irrespective of CD4 count
IAS (2012)
EACS (2013)
<350
Consider 350 – 500 and >500

10. Reducing onward transmission: Viral suppression among key population groups living with HIV in the United Kingdom. 19th Annual Conference of the British HIV Association (BHIVA) April 2013, Valerie Delpech, Alison Brown, Stephano Conti, Venkata Polavarapu, Zing Yin

11. Distribution of viral load among gay men living with HIV in the UK in 2010
HIV treatment as prevention among men who have sex with men in the UK: is transmission controlled by universal access to HIV treatment and care?
AE Brown*,ON Gill, VC Delpech, Article first published online: 28 July 2013, HIV Medicine, Volume 14, Issue 9, pages 563–570, October 2013

12. Reconstruction of HIV incidence from 2000
B: All condom use ceased C: ART provided at diagnosis
Figure 3. Reconstruction of incidence for counter-factual situations; (a) a scenario in which ART was never introduced, but patterns of sexual risk behaviour changes still occurred, (b) a scenario in which all condom use ceased in 2000, but with levels of anal sex as observed, (c) a scenario in which ART was provided at diagnosis from 2000, (d) a scenario in which testing rates increased (such that the proportion testing in the past year was 68% in 2010 compared with 25% as modelled for the actual incidence), and (e) a scenario of both higher testing and ART at diagnosis.
Phillips AN, Cambiano V, Nakagawa F, Brown AE, et al. (2013) Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic. PLoS ONE 8(2): e doi: /journal.pone

13. What is the potential impact of starting treatment early?
ART started at CD4 <500 could have reduced the proportion of PLWHIV with detectable viraemia from 42% to 38%
Halving the undiagnosed population could have led to to a decrease to 28%
“Unlikely early treatment will reduce HIV transmission unless undiagnosed population is substantially reduced”
Brown et al AIDS 2014 Jan 14;28(2):281-3

14. What is the potential impact of starting treatment early?
Extending ART to all diagnosed HIV infected MSM with CD4 <500 in 2010 would reduce proportion of infectious men from 35% – 29%.
Halving the proportion who are undiagnosed would further reduce this to 21%
“The effectiveness of treatment as prevention will be limited unless the undiagnosed population is reduced through frequent HIV testing and consistent condom use”
Brown et al AIDS 2014 Jan 14;28(2):281-3

15. Can we afford it?
Estimated annual population treatment and care costs:
£104 million in 1997
£483 million in 2006
£721 million in 2013
Mandalia et al PLoS One 2010; 5:e15677

16. Summary: TasP
The best evidence for effectiveness of an intervention to reduce transmission
Effectiveness depends on knowing HIV status and therefore interlinked with testing strategies
Cost may prohibitive

17. With limited resources do we focus on:
ART for HIV negative people?
ART for HIV positive people?
Reduced transmission
?cost
?adherence
?sexual behaviour
?other STIs
Reduced transmission
Reduced morbidity
Reduced mortality
Better quality of life
Low pill burden
Low toxicity