2. Immediate HIV treatment prevents new infections: causal evidence on the real-world impact of immediate vs. deferred ART in rural South Africa
Catherine Oldenburg, Jacob Bor, Frank Tanser, Guy Harling, Tinofa Mutevedzi, Maryam Shahmanesh, George Seage, Victor De Gruttola, Matthew Mimiaga, Kenneth Mayer, Deenan Pillay, Till Bärnighausen

3. Guy Harling has no conflicts of interest to declare

4. Benefits from immediate ART
WHO now recommends immediate ART for all patients regardless of CD4 count
Based on evidence from clinical trials
Prevention
Cohen et al. NEJM 2011, 2016
Health
Severe et al. 2011; Grinsztejn et al. 2014; Lundgren et al. 2015; Danel et al. 2015

5. Little evidence on real world impact
But potential gap between trial & real-world
Quality of care
Generalizability of population
Behavioral responses to treatment eligibility

6. Behavioral response to eligibility
Bor et al., CROI 2016

7. Little evidence on real world impact
But potential gap between trial & real-world
Differential quality of care
Generalizability
Behavioral responses to treatment eligibility
In real-world settings, observational data

8. Incidence in partners
And even when not in a carefully observed cohort or clinical study, ART substantially protects HIV-negative members of serodiscordant couples
Oldenburg, Bärnighausen, Tanser, Iwuji, De Gruttola, Seage, Mimiaga, Mayer, Pillay, Harling, Clin Infect Dis, 2016.

9. Incidence in the household
Beyond the couple, ART is associated with benefits for other-sex household members, associated with 45% reduction in hazard if all members on ART
Vandormael, Newell, Bärnighausen, Tanser. Lancet GH, 2014

10. Incidence in the community
And beyond the household, higher levels of ART coverage are associated with reduced population-level incidence.
Tanser, Bärnighausen, Grapsa, Zaidi, Newell. Science, 2013

11. Little evidence on real world impact
But potential gap between trial & real-world
Differential quality of care
Generalizability
Behavioral responses to treatment eligibility
In real-world settings, observational data
May be affected by unobserved confounders

12. Study aim
To estimate the causal, real-world effect of immediate eligibility for ART on: mortality, immune function, HIV incidence in the household We use Regression Discontinuity to identify causal effects
RD will allow us to

13. Study opportunity SA National Treatment Guidelines (2004-2011)
CD4 < 200 or Stage IV Initiate ART
CD4 ≥ 200 & no Stage IV Return in 6 months

14. Regression discontinuity design
True CD4 count: 200
True CD4 count: 200
True CD4 count: 200
Measured CD4: 188
Measured CD4: 195
Measured CD4: 207
- For example, CD4 counts and ART
We have 3 people presenting to care for the first time, all of whom have identical true CD4 counts
The first two, our measurement suggests CD4 < 200, so we initiate treatment
The last one, CD4 > 200, so we wait
Patients presenting just above vs. below 200 are similar on observed and unobserved characteristics…but assigned different exposures – as in an RCT.
This amounts to random assignment of people with CD4 counts close to 200 – so we can measure the LOCAL treatment effect of ART
Generate an unconfounded estimate, just like an RCT
Bor, Mutevedzi, Tanser, Newell, Bärnighausen. Epidemiology, Moscoe, Bor, Bärnighausen. Journal of Clinical Epidemiology, 2015.

15. Study setting Africa Centre for Population Health
We conducted our analysis in the Africa Centre for Population Health’s demographic surveillance area
2nd poorest district in SA
Population participating in surveillance for the past 16 years
Very high HIV prevalence and ongoing incidence; adult HIV prevalence of 30%

16. Study data
All DSA residents attending public sector clinics in Hlabisa sub-district
First CD4 count between Jan 2007 & July 2011
We see when ART initiated
We see regular CD4 counts
Mortality from demographic surveillance
HIV incidence from population HIV surveillance

17. CD4 counts at first clinic visit
Distribution of first CD4 counts between 50 and 350
Red line at 200 cells
No bunching below 200; does not suggest manipulation of CD4 counts

18. Continuity in baseline observables
Dots represent mean values within bins of width 10 cells/μl
Green lines are coefficients under and over 200 cells
Balance on covariates: as in RCTs

19. Immediate eligibility raises uptake

20. Immediate eligibility raises uptake
Risk difference: 0.32
95% CI (0.27, 0.38)
2/3 on ART within 6m just below 200; 1/3 on ART just above
So the cut-point does what we expected it to do
We will now show impact of this roughly doubling of ART, increase of 32 percentage points

21. Eligibility reduces mortality
Hazard Ratio = 0.65
95% CI (0.45, 0.94)
Bor, Moscoe, Mutevedzi, Newell, Bärnighausen, Epidemiology, 2014.

22. Eligibility improves immune health
Blue dotted line: 45 degrees. Same CD4 count at baseline and 12m
Clear cell rise for those eligible; fall off for those not eligible

23. Persistent impact on CD4 counts
75 cells/μl
- 50 cell difference at 1 year, 75 at years 2-3

24. ART eligibility reduces household HIV incidence
Hazard Ratio: 0.55
95%CI (0.35, 0.86)

25. Potential causal pathways
Biological: Reduced viral load
Behavioral: Changes in sexual behavior of household member on ART
Relational: Social influence on other household members
Proposed mechanisms for these reductions:
VL, both within a given relationship and across the community
Induced changes in ART client sexual behavior, arising directly from counselling or indirectly through experiences of ART or the healthcare system
Indirect impact of clients influencing family and friends, thus changing their behaviors

26. Generalizability All effects are local to CD4 count of 200
May be different at other CD4 count cut-offs
But similar effect seen for 350 cells/μl cut-off on ART uptake & retention
Bor et al., CROI 2016a, b

27. Conclusions
Immediate eligibility for ART is associated with lower mortality, improved immune function, reduced household HIV incidence
Real-world confirmation of trial results & causal confirmation of observational data
Both biological and behavioral pathways may contribute to the incidence effect

28. Acknowledgements
Community and staff at the Africa Centre for Population Health
KZN Provincial Department of Health
Funders:
Wellcome Trust (097410/Z/11/Z)
NIH (K01-MH105320, R01-AI112339, R01-AI124389, R01-HD084233, R01-HD058482, R25-MH083620, T32-DA013911)
You can reach the study team at:

29. Additional material

30. Robustness to bandwidth
Preferred Spec
+/- 150
ADD FIGURE SHOWING HRRD VS BW