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
“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”
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
Outline
• Biological plausibility
• Evidence
– Population studies
– Serodiscordant couple studies
– Modelling
• Transmission whilst undetectable
• PHI and possible impact on “Test and
Treat”
• Future information sources
Viral load determines risk of transmission
Evidence: HCW case control study
AZT
0.2
AIDS
6.4
Vessel
5.1
Visible blood
5.2
16.1
Deep
0
5
10
15
OR
Cardo DM et al. N. Engl. J Med 1997; 337:1485
20
Thai Study: no transmissions < 1049; Tovanabutra, JAIDS 2002
% Patients With Detectable
HIV in Semen
Semen HIV With ART
Controls (drug naive) n = 55
n = 114
Potent ART
100
80
p < 0.0001
p = 0.025
60
40
20
0
HIV RNA
Vernazza, Cohen et al. AIDS 2000
HIV DNA
ART reduces transmission by reducing viral load
Brighton phylogenetic
study
Fisher, AIDS 2010
HIV-1 MSM Cohort
(2000 - 2006)
n=1114
pol Sequence Available
n=859 (75%)
Recent HIV Infection
n=159 (10%)
Identified Most Likely Transmitter
n=41 (26%)
Recent HIV
n=10 (24%)
Chronic HIV
n=31 (76%)
Chronic HIV Infection
n=700
Brighton phylogenetic study
Factors associated with transmission
(Multivariable*)
Factor
Rate Ratio 95% CI
p-value
Viral Load (per log10 increase)
1.68
1.19 - 2.36
0.003
Recent Infection
3.43
1.52 - 7.73
0.003
STI during interval
5.64
2.65 - 12.02
0.0001
Age (per 5 years older)
0.68
0.54 - 0.85
0.0009
On HAART
0.28
0.05 - 1.44
0.13
*Poisson Regression Model - variables in model include calendar year as well as those above
Fisher, AIDS 2010
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
Meta-analysis: ART and viral load
and transmission
Attia, AIDS, 2009
Meta-analysis: ART and viral load
and transmission
92% reduction in HIV transmission with ART
Attia, AIDS, 2009
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
Partners in Prevention Study
Donnell, Lancet, 2010
Partners in Prevention Study
Donnell, Lancet, 2010
92% reduction in HIV transmission with ART
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
Models of ART and transmission
San Francisco
Katz, Am J Pub Health,
2002
Increase in risk behaviour in MSM will
outweigh benefit of ART
Australia
Clements, JAIDS, 2004 ART benefits outweighed by increased risk in
MSM
South Africa
Bertran, JAIDS, 2004
WHO guidelines: 12% reduction in incidence
US guidelines: 72%
Amsterdam
Bezemer, AIDS, 2008
Benefits of ART outweighed by increased risk
behaviour in MSM
British Columbia Lima, JID, 2008
67% reduction in incidence if 100% treated at
CD4 <350
Australia
Wilson, Lancet, 2008
ART rather than condoms may increase
incidence 4 fold
WHO
Granich, Lancet, 2009
Annual testing and universal ART could
reduce prevalence of HIV to <1%
Impact may be different for MSM and heterosexuals?
ART versus condoms ?
In serodiscordant male couple
after 100 anal contacts
Garnett &Gazzard, The Lancet, 27.7.2008, editorialcomment
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
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
Reducing viral load with ART to
undetectable prevents transmission
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
? Transmission whilst undetectable
(Brighton phylogenetic study)
Fisher, CROI 2009
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
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)
Rectal HIV Shedding
R Zucker man et al J Infect Dis. 2004 Jul 1;190(1):156-61.
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
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
?
Swiss Statement
“An HIV infected individual without an additional
STD and on antiretroviral therapy with
completely suppressed viraemia is sexually noninfectious 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
Ranges of HIV transmission risks
Oral sex3
Ejac
Sex under ART
STD
Vaginal sex1
Condom Use2
10-6
1Royce
10-5
et al, NEJM, 1997
Anal sex1
10-4
10-3
Risk per act
2Davis
1999
3Vittinghoff,
0.01
1999
0.1
After Vernazza, 2009
Ranges of HIV transmission risks
Oral sex3
Ejac
Sex under ART
Skiing in the Swiss Alps
STD
Vaginal sex1
Condom Use2
10-6
1Royce
10-5
et al, NEJM, 1997
Anal sex1
10-4
10-3
Risk per act
2Davis
1999
3Vittinghoff,
0.01
1999
0.1
After Vernazza, 2009
HPTN 052
(to report in 2016)
HIV-infected subjects with CD4 count 350-550 c/µL
Randomization
Immediate
ART
AZT+3TC+EFV
ART deferred until
200 < CD4 < 250
End points: i) Transmission events
ii) Clinical events (When to Start)
iii) ART toxicity
Http://www.hptn.org/research_studies/hptn052.asp
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)
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
• 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
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
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
Treatment as prevention: why?
Gus Cairns
Editor, HIV Treatment Update
3 April 2003
HIV diagnoses
24 November 2010
NAT Treatment as Prevention
Condom use in UK gay men
24 November 2010
NAT Treatment as Prevention
Treatment as prevention: evidence?
24 November 2010
Montaner, Lancet 376: 532 – 539, 2010
NAT Treatment as Prevention
BC study again
24 November 2010
NAT Treatment as Prevention
San Francisco
Das-Douglas, CROI 2010, abstract #33
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)
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
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 HIVpositive people
• ?Pilot study of ARV treatment
for high-risk HIV-negative
testers nested within TasP
project?
24 November 2010
NAT Treatment as Prevention
Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men. New Engl Jour Med 23 November 2010.