HIV : Test and Treat?

Transcription

1 HIV : Test and Treat? 14 th HIV Resistance Meeting Why now? Test and Treat What does it mean? Could it work-what is the evidence? What are the challenges? 1

2 Universal ART Access 2008 UNAIDS 33 million PLWHA 2.7 million new infections 2 million deaths from HIV related disease million on ART 5millionmore need treatment now (CD4<200) 2010WHO Guidelines (CD4 <350) takes this to 10million New infections outstrip Treatment by 5:2 IAS 2010 Treatment 2.0 i) Recognize and use HIV treatment as a tool for preventing new infections ii) Develop better combination antiretroviral medications and cheaper diagnostics tools iii) Find ways to lower other HIV-related costs iv) Expand the availability of HIV testing and build stronger links between HIV testing and care v) Encourage and support community leadership in expanding and improving local HIV responses. 2

3 Funding At the current rate of infection the projected costs of delivering and maintaining universal ART access is; $42 billion in 2010 $54 billion by 2015 Preventing the 3,550 HIV infections that were probably acquired, and subsequently diagnosed in the UK in 2008, would have reduced future HIV-related costs by more than 1.1 billion. Setting the scene If we don t do better with prevention we will never, never achieve universal access to HIV treatment because the number becoming infected is growing all the time. Kevin de Cock

4 What is Universal HIV test and treat? Increase Voluntary HIV testing to Universal levels Offer Immediate lifelong ART IRRESPECTIVE of CD4 count for all individuals testing HIV +ve Assumes: ART reduces transmission risk to zero and acceptability, feasibility, availability of testing and treatment strategies, infrastructure, operational staff and drug supply safe robust ART regimens, minimal failure limited drug resistance, toxicity repeated testing Ignores: Human rights issues: coercion, marginalisation of groups choosing not to comply or adhere or test Compensatory increased sexual disinhibition may counteract benefit Mathematical models Ro must be < 1 to eliminate infections at a population level Assume annual HIV testing 4

5 Test and Treat concept Granich et al 2009 Lancet ART: Potentiallymore efficacious than any of the previously evaluated prevention methods Are the underlying assumptions of the models correct? 10 5

6 Models assumptions It is possible to deliver approaching % population acceptance of HIV testing Of those diagnosed HIV+ve > % will accept immediate ART ART is fully suppressive of viral replication in >90% of individuals on therapy pvl< 50 copies = zero risk of transmission There will be no behavioural disinhibition Annual HIV VCT is sufficient to deliver an impact on transmission- IGNORES the role of acute infection Increased life expectancy, increases prevalence makes more years for potential onward transmission risk ART for Prevention: Assumptions=Results 1 st author (yr) Key assumptions Results Cohen and Gay, CID 2010 Blower (2000) Steady risk behavior levels; low resistance rate; 50% -90% ART coverage Lima (2008) 75% -100% ART coverage when CD4 < 200; stable adherence Law (2001) Fraser (2004) 2X-10X in infectiousness; 40% -70% in unsafe sex Viral load suppression on ART limits transmission; 66% in risk behavior Wilson (2008) Effective ART reduces viral load to < 10 copies / ml; decreased condom use Baggaley (2006) Treatment of all w/ AIDS & pre-aids; decreased risk-taking Granich (2009) Universal annual HIV testing & immediate treatment substantial in HIV incidence 37% -62% in HIV incidence Behavioral disinhibition could limit preventive benefit Behavioral disinhibition could limit preventive benefit Behavioral disinhibition could limit preventive benefit Only small number of infections averted African HIV epidemic could be ended 6

7 UTT models do not account for acute HIV infection Up to 20% of all new UK HIV infections are of recent acquisition (HPA 2008) In focused epidemics the contribution to onwards HIV transmission of recently infected individuals can be up to 50% 7

8 Treatment As Prevention: The Concerns ART does NOT stop viral shedding in the male or female genital tract. plasma viral load does NOT always equal genital tract viral load ART evokes resistance and it is possible that resistant variants will be transmitted In the real world ART may not provide the transmission prevention expected (Wang) Acute infection is a powerful force Sexual disinhibition may counter the effects of ART Is HIV transmission prevented by ART? Where is the evidence? 8

9 Mother to Child Transmission AZT % of infected children HAART < Adapted from Coovadia and Lallemant, NEJM Rakai Study: Transmission risk/ viral load Quinn et al. N Engl J Med 2000;342:

10 Results 3 heterosexual discordant couple studies in Africa Study A* Study B** Study C*** «before» «after» Condoms HAART - - Infections %/year * WawerM et al. Lancet 2009; 374: ** BunnellR et al. Abstract 29, 15th CROI, 2009 *** Donnell D, Lancet Couples studies Rwanda/Zambia 2,993 couples studied days follow-up (mean) ART use was not associated with increase sexual risk 175 transmission events, 4/175 from subjects receiving ART 80% reduced risk of HIV transmission Sullivan et al. CROI 2009 #52bLB IAS 2009 Chinese couple study 1,927 discordant couples in Henan followed ,396 index cases receiving FREE ART 84 seroconversionsdistributed equally among subjects on and off ART Wang Lu et al. IAS 2010, JAIDS in press Wang ThPDC102, IAS

11 Attia AIDS 2009 Meta-analysis of 47 studies of HIV heterosexual discordant couples showed zero transmissions for HIV pvl < 400 copies HIV RNA/ml but were compatible with 1 transmission / 79 person years HPTN 052/ACTG 5245 Can HIV Treatment Serve as Prevention? 12 sites, 9 countries 1763 discordant couples now in year 2/5 To determine the DURABILTYof ART in prevention of sexual transmission of HIV To better determine When to Start ART 11

12 Can population wide ART reduce viral load to confer a significant impact on HIV incidence? The evidence.. Ecological Studies of expanded HIV VCT and ART Proposed Benefit from Introduction of ART: San Francisco (Das PloS One, 2010) British Columbia (Montaner Lancet, 2010) Denmark (IAS, 2010) No benefit from Introduction of ART Amsterdam (CROI, 2010) France (CROI 2010) Australia (Sexual Health, 2008) Wang (IAS, 2010, JAIDS, in press) 12

13 Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. Das et al PlosOne2010 Mean CVL was calculated as the mean of the most recent viral load of all reported HIV-positive individuals in a particular community HIV VCT 72% ART uptake 90% How can we test the UTT strategy? Pilot, feasibility study first then Ecological trials Cluster randomised trials 13

14 Designing a UTT effectiveness trial What proportion of individuals within a population will accept HIV VCT? What proportion of those testing HIV+vewill accept immediate ART- what is immediate? What ART regimen is the least toxic, best tolerated with the greatest genital tract penetration, safest in pregnant and breastfeeding women and has the highest genetic barrier to drug resistance? What will be the outcome measure-hiv incidence-but there is no cross sectional incidence assay available-sample repeat testing What are the costs, risks, safety issues, rates of drug restance Implementation of testing Currently 80-90% of PLWHA in SSA DON Tknow their status 27% of PLWHA in UK don t know their status 14

15 Uptake of HIV testing Treat and we will test What frequency of testing is needed to prevent transmission? Annual 2-5 years (Dodd 2010 AIDS) How best to deliver testing? POCT, self testing work place, house-to-house, linkage with other services- TB, Malaria, Vaccination, GUM screens, opt out hospital settings How do we deliver Universal ART? 15

16 Treatment 2010 WHO treatment guidelines recommend ART for CD4 <350 Universal access for pregnant and breast feeding women BUT Inability to deliver ART for 5 million people now living in need of immediate ART When to Start? START trial CD4 > 500 immediate or defer Risks vs benefit of earlier ART are unknown Do we really understand all the issues of early ART? Pros Earlier treatment maybe beneficial to the individual Reduces the rates of TB (rate of TB increases by 0.42 cases/100pys per 100 fall in CD4 count Lawn et al CROI 2009) Automatically takes care of PMTC programs as all HIV+vewomen are on ART Reduces sexual transmission in monogamous HIV serodiscordant relationships Cons Lack of data on long-term risk of drug resistance Lack of data on risk of toxicity vsclinical benefit of longer ART exposure (START trial) Acceptability within communities where HIV status remains stigmatising Feasibility of operationally delivering ART to almost all the HIV+vepopulation (San Francisco MSM achieved >90% ART coverage to confer a reduction in incidence) Is this best use of resources? 16

17 Monitoring Monitoring /safety renal, liver, bone marrow (blood/urine) function Efficacy tests (CD4, RNA VL) Need for roll-out of low-cost point-of-care tests CD4, RNA VL, resistance testing Cost Lab capacity Impact on pace of roll-out Need for evidence-based monitoring DART CIPRA S. Africa Jinja Uganda 17

18 At what CD4 count would we need to start ART to deliver a significant reduction in population level transmission? Relationship between HIV testing frequency, CD4 count, and R 0 R 0 <1 18

19 But not all ART are equal What should we treat with? Sexual transmission requires drug genital tract penetration and reduction in genital tract viral loads to < 400 copies HIV RNA/ml Concentration of ART in the Female Genital Tract Results Depend on Drug Class RAL (400%) 19

20 Summary-much to do ART has the power to reduce transmission of HIV, but the exact magnitude of ART transmission suppression and its durability are unknown A combination strategy ha the most chance of successmale circumcision, sexual behaviour change, vaginal microbicides as well as UTT ART combinations designed for HIV prevention can be developed The population benefit of ART depends on durable transmission suppression the contribution of acute HIV infection Sexual mixing within a population Frequency of testing What studies are planned to test the strategy? Botswana Cohort Pilot (Essex) HPTN 065 in US-NYC, DC (El-Sadr, Mayer) PopARTUganda, Tanzania, Malawi, Zambia (Fidler, Hayes, Kamali, Kapiga, Ayles) HPTN Africa (Mastro, Hodder) Kenya(Little) ANRS TasPS Africa(Hirscheland Dabis) 20

21 Thanks J Weber R Hayes M Cohen A Fakoya R Granich, B Williams S Crowley PopARTcollaborators; A Kamali, P Kaleebu, H Ayles, D Watson-Jones, S Keeling, E Corbett, S Kapiga, S McCormack, R Tatoud, A Babiker, P. Piot 21