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Transmission risk between couples: the “science”

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

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Transmission risk between couples: the “science”

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  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

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

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

  9. ART reduces transmission by reducing viral load

  10. Brighton phylogenetic studyFisher, AIDS 2010

  11. Brighton phylogenetic studyFactors associated with transmission (Multivariable*) *Poisson Regression Model - variables in model include calendar year as well as those above Fisher, AIDS 2010

  12. 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

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

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

  15. Partners in Prevention StudyDonnell, 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

  16. Partners in Prevention StudyDonnell, Lancet, 2010

  17. Partners in Prevention StudyDonnell, Lancet, 2010 92% reduction in HIV transmission with ART

  18. 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

  19. Models of ART and transmission Impact may be different for MSM and heterosexuals?

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

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

  22. 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

  23. Reducing viral load with ART to undetectable prevents transmission

  24. 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

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

  26. 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

  27. 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)

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

  29. 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

  30. undetectable = un-infectious ? • Viral load determines risk of transmission √ • ART reduces transmission by reducing viral load √ • Reducing viral load with ART to undetectable prevents transmission ?

  31. 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

  32. Ranges of HIV transmission risks Oral sex3 Ejac Sex under ART STD Vaginal sex1 Condom Use2 Anal sex1 10-6 10-5 10-4 10-3 0.01 0.1 Risk per act After Vernazza, 2009 2Davis 1999 1Royce et al, NEJM, 1997 3Vittinghoff, 1999

  33. Ranges of HIV transmission risks Oral sex3 Ejac Sex under ART Skiing in the Swiss Alps STD Vaginal sex1 Condom Use2 Anal sex1 10-6 10-5 10-4 10-3 0.01 0.1 Risk per act After Vernazza, 2009 2Davis 1999 1Royce et al, NEJM, 1997 3Vittinghoff, 1999

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

  35. 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)

  36. 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 orvaginal intercourse together in the past month • Partners expect to have sex together again in the coming months

  37. 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

  38. 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

  39. 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

  40. Treatment as prevention: why? Gus Cairns Editor, HIV Treatment Update

  41. HIV diagnoses NAT Treatment as Prevention

  42. Condom use in UK gay men NAT Treatment as Prevention

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

  44. BC study again NAT Treatment as Prevention

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

  46. 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) NAT Treatment as Prevention

  47. 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 NAT Treatment as Prevention

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