The Biological Basis for HIV Transmission and Prevention HIV Transmission. Giuliana Zoboli S.C. Malattie Infettive ASMN di Reggio Emilia

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1 The Biological Basis for HIV Transmission and Prevention HIV Transmission Giuliana Zoboli S.C. Malattie Infettive ASMN di Reggio Emilia Reggio Emilia, 19 aprile 2013

2 Global Prevalence of HIV infection: 33.4 Million women 25% of new HIV infections Adult prevalence % 15.0% 39.0% 5.0% 15.0% 1.0% 5.0% 0.5% 1.0% 0.1% 0.5% 0.0% 0.1% not available 60% women >85% HIV Infections occur through genital and ano-rectal mucosal exposure

3 Contribution of Mucosal HIV-1 Invasion Sites to Global HIV-1 Infections in Adults Hladik F ed al. Nat Rev Immunol 2008; 8:

4 Biological Factors Affecting Perinatal Transmission of HIV Maternal HIV-1 RNA Placental Fetal Breast Feeding ART Rx Duration of Ruptured Membranes ART Rx C-Section

5 Effetti della ART sulla prevenzione 30 PACTG % riduzione della trasmissione % randomizzato, doppio cieco, 363 coppie madrebambino, gravide HIV+ (14-34 sett.), CD4 > 200/mL, non terapia precedente Placebo 8.3% ZDV Group (40/183) (13/180) Connors, NEJM 1994

6 N Engl J Med 1999;341: Maternal levels of plasma HIV RNA and the risk of perinatal transmission Mother s viremia of a non infected newborn Mother s viremia of an infected newborn No transmission if maternal viremia < 1000/ml 16.6% di rischio se HIV RNA è fra 1001 e 10000, 21.3% di rischio se HIV RNA è fra e 50000, 30.9%di rischio se HIV RNA è fra e , 40,6% di rischio se HIV RNA è maggiore di

7 Mother to Child Transmission AZT % of infected children HAART Adaptedfrom Coovadia and Lallemant, NEJM 2004

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9 PACTG 076 & USPHS ZDV Recs CDC HIV Testing Recs

10 HIV-1 Transmission in the Lower Female Genital Tract Hladik F ed al. Curr HIV/AIDS Rep 2009; 6:20-28

11 HIV-1 Transmission in the Lower Female Genital Tract Trapping of free HIV virions in the mucus covering the mucosa Attachment of hiv infected cells to the luminal surface of the mucosa which then secrete virions upon contact Penetration of virions into gaps between epithelial cells Capture of virions by Langerhans cells (LC) residing within the epithelium HIV fusion with intraepithelial CD4+ T lymphocytes followed by productive infection Transcytosis of virions through epithelial cells of the basal layer of the squamous epithelium Internalization of virions in the basal epithelial cells Hladik F ed al. Curr HIV/AIDS Rep 2009; 6:20-28

12 HIV-1 Transmission in the Lower Female Genital Tract Migration of infected donor cells and free virions along abrasions of the epithelium into the mucosal stroma Productive infection of stromal dendritic cells (DC) by HIV Internalization of virions into the endocytic compartments of stromal dendritic cell Passage of virus from stromal dendritic cell to CD4+ T lymphocytes across infectious synapse Massive productive infection of mucosal CD4+ T lymphocytes activated by contact with antigen presenting dendritic cells Binding and productive infection of stromal macrophages Migration of productively infected CD4+ T cells and DCs into the submucosa and the draining lymphatic and venous microvessels Migrating DC may originate from intraepithelial LCs or stromal DCs Hladik F ed al. Curr HIV/AIDS Rep 2009; 6:20-28

13 Am J Reprod Immunol 2011;65:

14 Am J Reprod Immunol 2011;65:

15 Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED INFECTED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PrEP Microbicides Vaccines ART PEP Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS HOURS 72h YEARS

16 Why Should Circumcision Prevent HIV Acquisition? Mucosa is replaced with epithelium Circumcision Reduced number of ulcers Elimination of phimosis Reduced target cells for HIV

17 Impact of Male Circumcision on HIV: Evidence from Observational Studies and RCTs Reduction of risk (95% CI) Overall ( 66, 48) 1 South Africa (RCT) 60 ( 76, 33) 1 Kenya (RCT) 59 ( 76, 30) 1 Uganda (RCT) 51 ( 82, 14) 7 Weiss et al. AIDS 2000, 14: Auvert et al. PLoS Med 2005(11): e Bailey et al. Lancet 2007; 369: Gray et al. Lancet, 2007, Reduction of risk (0%) 16 % reduction risk of HIV acquisition in MSM with insertive acts Sanchez J et al AIDS 2011, 25:

18 Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED INFECTED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PrEP Microbicides Vaccines ART PEP Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS HOURS 72h YEARS

19 Viral Load Predicts Heterosexual Transmission Quinn et al. NEJM. 2009;342(13):

20 HAART as PREVENTION Can HAART reliably reduce HIV transmission? What impact does HAART have on infected cells, in semen and vaginal tract? How should people in general and discordant couples be counselled about the capacity of HAART to prevent transmission?

21 HOW ANTIRETROVIRALS AFFECT HIV TRASMISSION Plasma HIV RNA Survival PLHIV Genital tract HIV Duration of infectiousness Transmission Transmission Issues:Access, Adherence, Prevention, Rx STIs

22 In January 2008 Swiss doctors and researchers (VERNAZZA et al.) Issueed Statement of Swiss Federal AIDS Commission: Heterosexuals : -in monogamous relationships -taking HIV treatment -who have undetectable VL (<40) in their blood Cannot pass HIV to an HIV-negative sex partner provided: -undetectable VL on HAART for at least six months -took their treatment properly (100% adherent) -they did not have a STD???

23 67% 1.8% 38% 16% Vernazza P et al AIDS 2000,14:

24 6.8% 30.5% 45.8% 54 % of women has detectable at least once in the genital tract 37% of women has detectable at least once in the genital tract when PVL was undetectable

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26 5% HIV-1 infected men had detectable HIV-RNA in the semen although they had undetectable HIV-RNA in blood whereas they were under HAART Marcelin AG. et al. AIDS 2008, 22:

27 Halfon P. et al, Plos one. May 2010

28 Discordant Couples Positive results: -Bunnel ( JAIDS, 2007 ) -Sullivan ( IAS, 2008 ) -Donnell ( Lancet, 2010 ) -Romero ( BMJ, 2010 ) -Reynolds (AIDS 2011) -Choen (HPTN 052 on going) Negative results: -Wang ( JAIDS, 2011 )

29 Lancet.Vol.375 June discordant couples 349 HIV+ partecipants started HAART 103 genetically linked transmissions 102 in partecipants not on HAART 1 in partner on HAART (18 days after starting ARVs) ART leads to 92% reduction in HIV transmission

30 HAART as Prevention in Rakai-Uganda Impact of antiretroviral therapy on HIV transmission among HIV discordant couples in Rakai, HIV transmissions occurred person years among couples not on ART, incidence: 9.2/100 py (95% CI ) No HIV transmissions occurred among the 32 couples on ART over 53.6 person years during periods when index partner was on ART Reynolds et al. AIDS 2011, 25:

31 HPTN discordant heterosexual couples 8 countries, 12 sites Randomization Immediate ART cells/uL AZT+3TC+EFV Deferred ART CD4 <250 Endpoints: i) HIV transmission to partners ii) OIs and clinical events iii) ART toxicity

32 Results HPTN cases of HIV infection among HIV negative partners 7 infections not linked to the HIV + partner 28 linked to HIV + partner through genetic analysis 4 infections are on analysis 27 in couples in which the HIV + partner wasn t on ARVs 1 in couple in which the HIV+ partner was on ARVs Immediate ART leads to 96% reduction in HIV transmission

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34 Sexual Transmission of HIV According to Viral Load and Antiretroviral Therapy: Systematic Review and Meta-Analysis Attia s. et al. AIDS 2009, 23:

35 Sexual Transmission of HIV According to Viral Load and Antiretroviral Therapy: Systematic Review and Meta-Analysis ART leads to 92% reduction in HIV transmission Attia s. et al. AIDS 2009, 23:

36 Easier, less toxic and more potent therapy is part of the rationale for earlier HAART

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39 Test and Treat-Different Models AUTHOR KEY ASSUMPTIONS RESULTS Blower (2000) Steady risk behavior levels; low resistance rate; 50% - 90% ART coverage Substantial in HIV incidence Lima (2008) 75% - 100% ART coverage when CD4 < 200; stable adherence 37% - 62% in HIV incidence Law (2001) Fraser (2004) 2X-10X in infectiousness; 40% - 70% in unsafe sex Viral load suppression on ART limits transmission; 66% in risk behavior Behavioral disinhibition could limit preventive benefit Behavioral disinhibition could limit preventive benefit Wilson (2008) Effective ART reduces viral load to < 10 copies / ml; decreased condom use Behavioral disinhibition could limit preventive benefit Baggley (2006) Granich (2009) Treatment of all w/ AIDS & pre-aids; decreased risk-taking Universal annual HIV testing & immediate treatment Only small number of infections averted South African HIV epidemic could be stopped Cohen M.S and Gay C.L, CID 2010 (suppl 3): 85-95

40 CID 2011;52: (15 March) ~50% ~80% 19 % US HIV people

41 Test and Treat Should Work But It s very hard to get everyone tested It s very hard to get everyone linked to care It s very hard to have everyone adherent to treatment

42 Billions de $ 30 Costs of HAART? Small investment Great savings Lima VD et al. Expanded Access to Highly Active Antiretroviral Therapy: A Powerful Strategy to Curb the HIV Epidemic; JID 2008; volume 198, July 1. Hogg et al. Unpublished, 2006

43 ECOLOGICAL STUDIES Showing benefit -San Francisco ( Das et al, Plos One,June 2010, CROI 2011 abs.1022 ) -British Columbia ( Montaner, Lancet 2010 ) Not showing benefit -Amsterdam ( Jansen et al. AIDS 2011 ) -Australia ( Law et al. JIAS 2011 )

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46 CROI 2011, poster 484 ALIVE Cohort IDU Baltimore since 1996 HIV incidence declined by 68% every log decline in CVL HIV incidence declined by 5% for each 1% increase in proportion of HIV+ on HAART

47 Number of active HAART participants Number of nev HIV diagnoses +547% -52% July

48 For 100 additional individuals on HAART, the number of new HIV cases decrease by a factor of 0.97 For 1 log 10 decrease in viral load, the number of new HIV cases decrease by a factor of July

49 1.73 Decrease >12 fold 0.13 Annual Incidence rate of drug resistence detected for any antiretroviral category and for individual drug classes. CID 2010:50 ( 1 January )

50 2010 from HAART as prevention to The ART of prevention

51 Antiretroviral in Blood vs.genital tract

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53 Tenofovir gel reduced HIV acquisition of 39% overall High adherers: 54% (>80% gel adherence) Intermediate adherers: 38% (50-80% adherence) Low adherers: 28% (<50% adherence) No K65R found in seroconverters with standard sequences

54 Current PrEP trials Trial Product Target population Sites CDC Bangkok tenofovir trial Viread 2,400 IDUs Thailand iprex trial Truvada 3,000 MSM Peru, Ecuador, US, S Africa and Brazil PartnersPrEP trial VOICE FemPrEP Viread & Truvada Tenofovir gel, Viread & Truvada Viread & Truvada 4,700 discordant couples 5,000 women 3,900 women Kenya, Uganda Malawi, South Africa, Uganda, Zambia, Zimbabwe Kenya, Malawi, South Africa, Tanzania, Zambia

55 Tenofovir + Emtricitabine: TDF Truvada FTC Truvada Limitata presenza di resistenza virale Lunga emivita intracellulare: > 60 ore + Ottima penetrazione seminale Rapida modalità d azione nella fase di pre-integrazione Premesse: studi su animali con PEP e PrEP hanno dimostrato superiorità di efficacia di Truvada rispetto a Tenofovir monoterapia anche in termini di sviluppo di Resistenza

56 2499 MSM, randomized 1:1 daily oral FTC/TDF vs placebo 11 sites ( Brazil, Ecuador, Peru,US, Thailand,S.Africa Young high risk MSM (50%<25years, median 18 partners in 12 weeks prior to enrollment) Completed 2010:excellent safety profile (nausea first month) Small decrease BMD (MULLIGAN CROI LB )

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58 . ADHERENCE IS CRITICAL TO EFFICACY

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61 Topical Antiretroviral Therapy CROI 2011, 34LB: oral vs 1% TDF rectal gel phase 1 study; specific rectal formulation needed (adverse events and low protection). CROI 2011, 35LB: oral vs.vaginal vs.oral+vaginal TDF; less side effects with vaginal gel ( nausea, diarrhrea, headache ), US women preferred tablets, African women both. 100X higher levels of TDF in vaginal biopsies with topical compared to oral. CROI 2011, abs30: Raltegravir gel associated with high protection against vaginal infection in macaques. RAL late action allows its use up to 10 hours after challenge.

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64 CONCLUSIONS HAART for prevention? Surely an issue but not to work alone What are barriers to Treatment as Prevention? - Linkage to care - Adherence to HAART ( and which HAART?) - HIV resistance ( reflecting drug selection and adherence) - Acute, early infection and/or high viral load Pre and post exposure prophylaxis? Which drugs, how, where and when to be delivered Male circumcision: it works but only in men! Condoms usage reduced HIV transmission by 78% (Hughes, et al, CROI 2011,Abstr 135 )

65 Grazie per l attenzione!