1. Transmission risk between couples: the “science” Martin Fisher Brighton and Sussex University Hospitals NHS Trust Gus Cairns National AIDS Manual

2. The “non-science” Swiss Statement “An HIV infected individual without an additional STD and on antiretroviral therapy with completely suppressed viraemia is sexually non-infectious i.e. he/she does not pass on HIV through sexual contact”

3. undetectable = un-infectious ? 1.Viral load determines risk of transmission 2.ART reduces transmission by reducing viral load 3.Reducing viral load with ART to undetectable prevents transmission

4. Outline Biological plausibility Evidence –Population studies –Serodiscordant couple studies –Modelling Transmission whilst undetectable PHI and possible impact on “Test and Treat” Future information sources

5. Viral load determines risk of transmission

6. Evidence: HCW case control study Cardo DM et al. N. Engl. J Med 1997; 337:1485

8. Thai Study: no transmissions < 1049; Tovanabutra, JAIDS 2002

9. HIV RNAHIV DNA 0 20 40 60 80 100 % Patients With Detectable HIV in Semen n = 55 n = 114 Controls (drug naive) Potent ART p < 0.0001 p = 0.025 Vernazza, Cohen et al. AIDS 2000 Semen HIV With ART

10. ART reduces transmission by reducing viral load

13. Brighton phylogenetic study Fisher, AIDS 2010

14. Brighton phylogenetic study Factors associated with transmission (Multivariable*) FactorRate Ratio95% CIp-value Viral Load (per log 10 increase)1.681.19 - 2.360.003 Recent Infection3.431.52 - 7.730.003 STI during interval5.642.65 - 12.020.0001 Age (per 5 years older)0.680.54 - 0.850.0009 On HAART0.280.05 - 1.440.13 *Poisson Regression Model - variables in model include calendar year as well as those above Fisher, AIDS 2010

15. Brighton MSM phylogenetic study RR of transmission 1.68 per log viral load higher Increased likelihood of transmission: –With “recent” infection ( RR 3.43) 2% of follow-up time but 24% of transmissions –with STI (RR 5.64) Reduced likelihood of transmission on ART (RR 0.28) –58% of follow-up time but 7% of transmissions –2 transmissions on “fully-suppressive” HAART during 3556 person years follow-up 1 likely to have occurred whilst viral load declining Fisher, AIDS 2010

16. Systematic Review 252 published articles and abstracts –14 considered to be eligible –7 articles, 7 abstracts –Most studies in heterosexuals and in Africa No studies that fulfilled the full criteria of the Swiss Statement Upper CI for transmission on ART: 1.09/100py Upper CI for transmission with VL <400 copies: 1.27/100py No cases of transmission where VL <40 “Unable to prove or disprove the Swiss Statement” Attia, AIDS 2009

17. Meta-analysis: ART and viral load and transmission Attia, AIDS, 2009

18. Meta-analysis: ART and viral load and transmission Attia, AIDS, 2009 92% reduction in HIV transmission with ART

19. Partners in Prevention Study Donnell, Lancet, 2010 Setting: 7 SSA countries (2004-2007) 3381 heterosexual couples Index seropositive for HIV and HSV-2 –study aim was role of HSV suppressive therapy Couples followed for 24 months HIV testing: –HIV +ve partner: HIV VL baseline, 3,6,12 and 24 months –HIV -ve partner: 3 monthly HIV testing –Phylogenetic linkage of HIV transmissions

20. Partners in Prevention Study Donnell, Lancet, 2010

21. 92% reduction in HIV transmission with ART

22. ART not always effective? Wang et al, JAIDS, 2010 Setting: Henin Province China (2006-2008). 1927 heterosexual couples HIV testing: –HIV positive partner: No HIV VL data –HIV negative partner: 6/12 HIV testing –No phylogenetic linkage of HIV transmissions 84 seroconversions in 1927 couples (4918 PY follow up) No statistical significant difference in seroconversions between spouse on ART (4.8%) and not on ART (3.2%) (p=0.12) No data on adherence (previous studies 66% poor adherence) Not using condoms (RR 8.42 [4.8, 14.6]) and increased frequency sexual activity (5.13 [2.76,9.5]) associated with transmission

23. Models of ART and transmission San FranciscoKatz, Am J Pub Health, 2002 Increase in risk behaviour in MSM will outweigh benefit of ART AustraliaClements, JAIDS, 2004ART benefits outweighed by increased risk in MSM South AfricaBertran, JAIDS, 2004WHO guidelines: 12% reduction in incidence US guidelines: 72% AmsterdamBezemer, AIDS, 2008Benefits of ART outweighed by increased risk behaviour in MSM British ColumbiaLima, JID, 200867% reduction in incidence if 100% treated at CD4 <350 AustraliaWilson, Lancet, 2008ART rather than condoms may increase incidence 4 fold WHOGranich, Lancet, 2009Annual testing and universal ART could reduce prevalence of HIV to <1% Impact may be different for MSM and heterosexuals?

24. ART versus condoms ? Garnett &Gazzard, The Lancet, 27.7.2008, editorialcomment In serodiscordant male couple after 100 anal contacts

25. ART versus condoms ? Garnett &Gazzard, The Lancet, 27.7.2008, editorialcomment In serodiscordant male couple after 100 anal contacts 90% reduction in HIV transmission with ART

26. Selective condom use? Hallett, Sex Transm Infect, 2010 Modelling based on data from Amsterdam MSM cohort Transmission within serodiscordant MSM couples according to: –ART –Viral load measurement frequency –Frequency of condom use Best protection: ART and 100% condom use Condom use only if VL measurement >3 months ago more effective than intermittent condom use Implications for frequency of viral load measurement / HIV follow-up

27. Reducing viral load with ART to undetectable prevents transmission

28. Transmission when undetectable ? MTCT (UK) [Townsend, CROI 2008] –3/2202 (0.1%; 2 intrauterine transmission) MSM (Germany) [Sturmer, Antiviral Therapy 2008] –Transmission through UPAI while <50 –Phylogenetic “confirmation” –No documented confirmation of previous negative test MSM (US) [reported by Bernard, ATU, 2008] –Transmission through APAI while VL <50 –No phylogenetic confirmation –UPOI with CMP

29. ? Transmission whilst undetectable (Brighton phylogenetic study) Fisher, CROI 2009

30. Why might transmission occur whilst “undetectable”? Viral load “cut off” Adherence / virological rebound Penetration of ART into genital tract Genital tract VL versus plasma Rectum versus plasma Sexually transmitted infections

31. Genital Shedding Genital tract viral load parallels plasma viral load –BUT not always –STIs may increase genital tract VL off ART Data on ART less clear ? 8x more likely to shed on ART (Winter, STIs 1999) Some individuals have detectable genital tract VL whilst “undetectable” on ART –12/25 in semen; 4 >5000 copies (Seth, CROI 2009) –4% detectable in semen (Marcelin, CROI 2009) –27/83 (33%) of women detectable in genital tract when <500 in plasma; 74% on ART (Kovacs, Lancet 2001) –52% detectable in genital tract when <80 in plasma (Cu-Uvin reported by Taylor 2008) –Detectability in female genital tract associated with <100% adherence (Graham, JID, 2010)

32. R Zucker man et al J Infect Dis. 2004 Jul 1;190(1):156-61. Rectal HIV Shedding

33. Role of undiagnosed and primary HIV in onward transmission Undiagnosed HIV: US: 54% of new infections come from 25% undiagnosed Marks, AIDS 2006 Amsterdam: 90% from 24% Bezemer, AIDS 2008 Brighton: 76% from 30% Fisher, AIDS 2010 Primary HIV Infection: High viral load Infectivity increased ? 10-100x PHI accounts for 10-50% of onward infections

34. undetectable = un-infectious ? 1.Viral load determines risk of transmission √ 2.ART reduces transmission by reducing viral load √ 3.Reducing viral load with ART to undetectable prevents transmission ?

35. Swiss Statement “An HIV infected individual without an additional STD and on antiretroviral therapy with completely suppressed viraemia is sexually non- infectious i.e. he/she does not pass on HIV through sexual contact” provided that the following conditions are fulfilled: Complies with ART, <50 for 6 months, no STI

36. Ranges of HIV transmission risks 10 -6 0.0110 -4 10 -5 10 -3 0.1 Anal sex 1 Vaginal sex 1 Sex under ART 1 Royce et al, NEJM, 1997 Ejac STD Risk per act Oral sex 3 3 Vittinghoff, 1999 Condom Use 2 2 Davis 1999 After Vernazza, 2009

37. Ranges of HIV transmission risks 10 -6 0.0110 -4 10 -5 10 -3 0.1 Anal sex 1 Vaginal sex 1 Sex under ART 1 Royce et al, NEJM, 1997 Ejac STD Risk per act Oral sex 3 3 Vittinghoff, 1999 Condom Use 2 2 Davis 1999 After Vernazza, 2009 Skiing in the Swiss Alps

38. HPTN 052 (to report in 2016) HIV-infected subjects with CD4 count 350-550 c/µL Immediate ART ART deferred until 200 < CD4 < 250 AZT+3TC+EFV End points: i) Transmission events ii) Clinical events (When to Start) ii) Clinical events (When to Start) iii) ART toxicity iii) ART toxicity Randomization Http://www.hptn.org/research_studies/hptn052.asp

39. A study in HIV serodifferent partnerships to investigate factors associated with consistent condom use and to estimate the rate of transmission of HIV Partners of people on ART: a New Evaluation of the Risks (PARTNER study)

40. Design Observational study in which HIV serodifferent partnerships will be followed over time, with 3-6 monthly reporting of transmission risk behaviour and HIV testing for the HIV negative partner Key Inclusion Criteria HIV+ partner on ART (regardless of viral load) Partners have had unprotected penetrative anal or vaginal intercourse together in the past month Partners expect to have sex together again in the coming months

41. N=1650 partnerships across Europe London –Charing Cross, Dean Street, Homerton, Kings, Kobler, Mortimer Market, North Middlesex, St Mary’s, St Thomas’, West Middlesex Birmingham, Brighton, Bristol, Cardiff, Coventry, Edinburgh, Leicester, Manchester

42. Antiretrovirals, sexual transmission risk and attitudes Observational questionnaire study of about 3500 HIV outpatients at 5 UK clinical centres. Questionnaire data linked to virological and clinical information. Aims to assess, among HIV-diagnosed individuals: Current levels of sexual risk behaviour (recent unprotected sex with HIV-negative or unknown status partner) Beliefs about transmission risk Impact of antiretroviral treatment use and viral suppression on sexual risk behaviour and beliefs Attitudes to use of early ART

43. Summary Viral load strong predictor of transmission ART reducing viral load to undetectable significantly reduces transmission Transmission whilst undetectable may occur (rarely) More data expected (including UK) ART likely to play a role in combination HIV prevention

44. 3 April 2003 Treatment as prevention: why? Gus Cairns Editor, HIV Treatment Update

45. 24 November 2010 NAT Treatment as Prevention HIV diagnoses

46. 24 November 2010 NAT Treatment as Prevention Condom use in UK gay men

47. 24 November 2010 NAT Treatment as Prevention Treatment as prevention: evidence? Montaner, Lancet 376: 532 – 539, 2010

48. 24 November 2010 NAT Treatment as Prevention BC study again

49. 24 November 2010 NAT Treatment as Prevention San Francisco Das-Douglas, CROI 2010, abstract #33

50. 24 November 2010 NAT Treatment as Prevention What would it take in San Francisco? In San Francisco 85.5% are diagnosed of whom 78% are linked to care of whom 90% are on ARVs of whom 72% are undetectable = 43.2% of people with HIV in San Francisco have an undetectable viral load (due to treatment)

51. 24 November 2010 NAT Treatment as Prevention Imperial College mathematical model Getting 80% of people with CD4 under 350 on treatment would be enough to reduce transmission by >90% if: Lower-risk pops tested every 2-3 years High-risk pops test every 6m Dodd PJ, Garnett GP, Hallett TB. Examining the promise of HIV elimination by 'test and treat' in hyperendemic settings. AIDS 24: 729-735, 2010

52. 24 November 2010 NAT Treatment as Prevention A wild card: PrEP IPrEx study, results 2 days ago 44% efficacy on 51% adherence Potentially 70-90% efficacy: cf condoms Practical? Affordable? Applicable? Dangerous? We may need to start thinking of ARVs-as-prevention for HIV-negative as well as HIV- positive people ?Pilot study of ARV treatment for high-risk HIV-negative testers nested within TasP project? Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men. New Engl Jour Med 23 November 2010.