What do models estimate to be the impacts on HIV incidence of various percentages of people

1. National AIDS Trust Treatment as Prevention Seminar 25th November 2010 Southwark Cathedral, London What do models estimate to be the impacts on HIV incidence of various percentages of people with HIV on ART ?

2. Policy of initiation of treatment at CD4 counts > 350 may require cost justification • Death rate ~ 5.2 per 1000 person years • If early ART reduces risk by 50% => • risk reduction 2.6 / 1000 person years 1 death averted per 385 person years of ART • Will initiation of ART in people with CD4 count > 350 / 500 • be funded ? - Assessment of cost-effectiveness requires a model that takes account of reductions in incidence Study group on Death Rates at High CD4 count in ART naïve people. Lancet 2010

3. Association between number on HAART and new HIV diagnoses Montaner et al, Lancet 2010

4. Association between mean “community” viral load and new HIV infections Das et al, PLOS One 2010

5. High rates of HIV testing but rising incidence in gay men in Australia ~ 90% of gay men have been tested for HIV Wand et al, 2010, Prestage et al, 2008

6. 1980 2000 2020 2040 Granich et al, Lancet 2008

7. Models of the impact of ART on transmission ART can function as an effective prevention tool, even with high levels of drug resistance and risky sex Velasco-Hernandez JX, Gershengorn HB, Blower SM. Lancet Inf Dis 2002 The use of treatment as prevention has the potential to reduce HIV epidemics only if consistent condom use is maintained. Wilson et al, Lancet 2008 ART is predicted to have individual and public health benefits ...but the benefit can be lost by residual infectivity or …… sexual disinhibition... Abbas UL, Anderson RM, Mellors JW. JAIDS 2006 ART cannot be seen as a direct transmission prevention measure, regardless of the degree of coverage Baggaley RF, Garnett GP, Ferguson NM. PLoS Med 2006 Expansion of HAART (amongst those with CD4 < 200 / < 350) led to substantial reductions in the growth of the HIV epidemic and related costs Lima et al JID 2008

8. Predicted effects on HIV incidence depend on • assumptions on: • - Testing coverage and frequency • Effect on individual health of early ART • Feasibility of identifying people in primary infection • Durability of adherence / viral load suppression on ART • Development and transmission of drug resistant virus • Change in unprotected sex due to HIV diagnosis • Change in unprotected sex due to viral suppression • Extent of reduction in infectivity with ART

9. HIV synthesis model Creates a ‘dataset’ of the course of infection and therapy for individual simulated patients. Years from infection 0 0.25 0.5 0.75 1.00 1.25 Fixed variables Variables updated at infection over time Calendar date Age Viral load CD4 count Risk of AIDS / death Use of specific ARVs Resistance mutations Calendar date Age at infection Gender Primary resistance

10. HIV progression in absence of ART Viral load CD4 count AIDS Age PCP prophylaxis Death from HIV Gender Death from other cause Assumed 1.5- fold increased Phillips et al, HIV Medicine 2007; Lancet 2008

11. Current adherence # Active drugs in regimen Switch to next line of ART Failure of current line of ART Effect of ART Acquisition of new resistance mutations Time on current regimen CD4 counts CD4 count Death from HIV* Viral load AIDS* *influenced by age and PCP prophylaxis also Phillips et al, HIV Medicine 2007, Lancet 2008

12. Effect of stopping ART Time off ART CD4 counts CD4 count Loss from majority virus of acquired resistance mutations Death From HIV* Viral load AIDS* Probability of resuming ART Other processes include: - Loss to follow-up - Substitution of drugs due to toxicity *influenced by age and PCP prophylaxis also Phillips et al, HIV Medicine 2007, Lancet 2008

13. Fit to observed data Observed Modelled Natural history AIDS by 10 years 46% 48% Median CD4 count at diagnosis of AIDS ~ 40 35 % dead by 1 year from initial AIDS 40% 45% Effect of ART Virologic failure by 7 years 27% 29% >1 resistance mutation by 7 yrs 19% 25% Rate of viral rebound in those with < 50 cps/mL 3-6% per yr 6% per yr >1 resistance mutation to 3 classes by 6 yrs 4% 6% Mean CD4 count increase at 3 years 273 270 Phillips et al, HIV Medicine 2007

14. HIV transmission synthesis model: Heterosexual epidemic in southern Africa Creates a ‘dataset’ of the lifetime experiences of ~50,000 people in a population, aged over 15. Years from 1985 1985 1985.25 1985.5 1985.75 1986.00 1986.25 Additional variables updated over time • e.g. • Calendar date • Infection with HIV • Sexual risk behaviour: • Long term partnership status • Number of new partners

15. Risk of HIV infection in uninfected subject Number of new partnerships formed by HIV+ people Subject Concurrent HIV+ population Current viral load of infected partner Number of new partners Number of new partners who are HIV+ Probability of HIV infection Age Gender Long term partner HIV+ Long term partnership status Incidence and prevalence of HIV in people with long term partnerships Risk of infection also depends on current STI

16. Comments - In southern African heterosexual epidemic setting: Assuming that unprotected sex with long term partners will reduce upon HIV diagnosis, a policy of frequent testing is likely to be beneficial for incidence, regardless of whether ART initiation threshold is CD4 200, CD4 350 or higher. - Plans to adapt this model for MSM in UK

17. Conclusion Models so far have demonstrated that intensive HIV testing with early ART initiation can, in principle, lead to substantial reductions in incidence if certain conditions hold. Models required now are ones that will give as realistic and detailed assessment as possible of the predicted impact of frequent testing and early ART on HIV incidence, and thus enable estimation of cost-effectiveness of the approach.

18. Acknowledgements Valentina Cambiano Geoff Garnett Deenan Pillay Marco Vitoria Diane Bennett Deenan Pillay Jens Lundgren Current funding from National Institute for Health Research Programme Grant