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Treatment As Prevention

The Pros. Treatment As Prevention. The Paper that started the fire. Granich, RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009; 373: 48-57.

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Treatment As Prevention

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  1. The Pros Treatment As Prevention

  2. The Paper that started the fire.. Granich, RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009; 373: 48-57.

  3. Treatment as Prevention: The Theory • Transmission only occurs from persons with HIV • On an individual level, viral load is single greatest risk factor for HIV transmission • ART can lower viral load to undetectable levels • The “proof of concept”: ART in the prevention of mother to child transmission (PMTCT) • Important key to the success of PMTCT (in the developed world) is the identification of the HIV positive individual • Observational evidence of transmission reduction among heterosexual couples • Growing body of evidence suggests benefits from earlier ART initiation significantly outweigh risks on an individual level.

  4. <400 <400 <400 >50 000 >50 000 >50 000 400-3499 400-3499 400-3499 3500-9999 3500-9999 3500-9999 10 000-49 999 10 000-49 999 10 000-49 999 HIV Viral Load & Transmission 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 Transmission rate per 100 Person-Years 10 5 0 HIV-1 Viral load (RNA copies/ml) in the HIV-Infected Partner Quinn et al. NEJM. 2009;342(13):921-929.

  5. HIV Viral Load & Transmission (2) Attia S, et al. AIDS 2009 Jul 17;23(11):1397-404.

  6. PACTG 076 & USPHS ZDV Recs CDC HIV Testing Recs • Important Caveats: • Transmission rates are higher for MTCT than sexual transmission • Pregnancy provides a defining event to encourage asymptomatic individuals to access testing.

  7. So What is the Universal Test & Treat Model? The Granich Paper Short Review • Key Concept: R0 – The number of secondary infections resulting from one primary infection in an otherwise susceptible population • Key to getting HIV epidemic under control is to get R0<1 • Key Question:Under what conditions could R0 be reduced to <1? • Conclusions:To reduce R0<1, adults & adolescents would need to be tested approximately once yearly and start ART at CD4 counts >900 cells/mm3. • Mean CD4 after seroconversion in South Africa = 884 cells/mm3 • When testing once yearly and starting ART at: • 200 cells/mm3: Reduces R0 to 4 • 350 cells/mm3: Reduces R0 to 3 • 500 cells/mm3: Reduces R0 to 2.5

  8. But before jumping “all in”… • There are concerns with the Granich model: • Assumes 40% effect from other prevention activities • Homogenous population • “Optimistic” cost assumptions • There are (obvious) concerns with implementation • Even under “optimistic” assumptions: Cost-prohibitive? • Concerns with resistance, behavioral disinhibition, human rights, etc…. • However, the purpose of the paper was to predict under which conditions “elimination” could be possible • Can realize these conditions? If so, how? Should Treatment play a larger role in Combination Prevention?

  9. Why Should ART be part of a combination prevention strategy? Proven Efficacy with Measurable Effect. Partners-in-Prevention Study: • 102 of 103 cases of confirmed linked HIV transmission occurred in couples with HIV-infected partner not receiving ARV therapy • 92% lower HIV transmission risk when HIV-infected partner on ART • Transmissions do occur among people with low CD4 Donnell D, Baeten J, Kiarie J, et al. Heterosexual HIV-1 Transmission after initiation of ART: a prospective cohort analysis. Lancet; published online May 27, 2010.

  10. Why Should ART be part of a combination prevention strategy? Additional Benefits Outside Prevention • Better CD4 Response, reduction in TB, other OIs, non-HIV related mortality and associated costs • While this by itself is not an effective argument to use treatment as prevention of HIV, it helps break down a longstanding barrier to wider use of ART. • Perhaps more importantly - everyone will need ART at some point: • Mean time to needing ART from seroconversion among those with CD>350  3 years3 • Why not start a year or two earlier? 1. When to start consortium.Lancet 2009 Apr 18;373(9672):1352-63 2. Severe P, Jean Juste MA, et al. Early vs Standard antiretroviral therapy for HIV-infected adults in Haiti. NEJM 2010; 363: 257-265. 3. Wolbers M, et al. Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating ART: The CASCADE Cohort. PLOS Medicine 2010; 7(2): e1000239.

  11. Why Should ART be part of a combination prevention strategy? • Prospective cohort study of home-based ART in a rural community in Uganda (n=926)1: • Reduced median VL (122k to <50 copies/mL) and estimated HIV transmission rate (from 46 to 1 per 1000 PY) • Risky sex decreased by 70% (P=0.002) • Prospective study of discordant couples in Zambia2: • Infection rate (per 100) decreased from 3.4 to 0.7. • Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05); Both ART and change in behavior independently reduced HIV transmission Change in Number of New Partners following VCT in Zimbabwe.3 Ancillary prevention benefits. BunnellR, et al. AIDS. 2006;20(1):85. 2. Sullivan CROI 2009 3. Cremin I, et al. AIDS Beh. 2010; 14: 708-15.

  12. The Question isn’t “Whether”, it’s “How”? • Know your Epidemic: There are different dynamics of transmission in different populations: • While we know ART is effective in prevention of HIV transmission, you need to prove that the specific intervention can be effective as implemented • However, this is true of all prevention interventions. • We do have a good track record of implementing treatment programs and ensuring good outcomes; and we have rigorous prospective data demonstrating a measurable prevention effect. Dodd P, Garnett G, Hallett T. Examining the Promise of HIV Elimination by ‘test & treat’ in hyperendemic settings. AIDS. 2010; 24(5): 729-735.

  13. My Take • Treatment can be used as part of a combination prevention strategy. However – it can’t be the only strategy. • Cost is a significant barrier • Treatment strategies alone have limited impact on acute transmission • Not enough is known about effects on resistance and risk compensation • Focus should be on better implementation of existing programs rather than expansion of treatment to higher CD4 thresholds. • If we can’t instantly identify the acutely infected, the biggest impact of VL reduction through ART comes from those with low CD4 counts. • For consideration: • Modified “test & Treat” in certain communities (most likely communities with good coverage, high health-seeking behavior, and favorable population dynamics)? • CSWs? Some MSM communities? • Serodiscordantcouples?

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