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1
Anti-HIV Drugs for Prevention
Bernard HirschelDivision of HIV/AIDS
Geneva University HospitalGeneva, Switzerland
2
Prevention at an Impasse
• Sexual behaviour• Condoms• Circumcision• Microbicides• Vaccines
3
The theory is just fine…
Perfect use0
20
40
60
80
100
Estimated rate of HIV after10 years’ cohabitation in a
heterosexual couple alwaysusing condoms
Adapted from W. Cates, FHI
4
Practice rather less so…
Perfect use Typical use0
102030405060708090
100
Estimated rate of HIV after10 years’ cohabitation in a
heterosexual couple at typicalrates of condom use
Adapted from W. Cates, FHI
5
ART: potentially more efficacious(than any of the previously evaluated prevention
methods)
6
« Rakai » Study: Transmission risk as a function of plasma viral load
Quinn et al. N Engl J Med 2000
No transmission if VL « undetectable »
7
Mother to Child Transmission
< 1994 1996 2000 20040
5
10
15
20
25
30
AZT
HAART% ofinfected children
Adapted from Coovadia and Lallemant, NEJM 2004
8
Effect of HAART on heterosexual transmission
• 476 heterosexual couples in Madrid• The “index” patient was HIV +, and consulted
between 1989-2008• Among their sexual partners, the only risk factor
for HIV was exposure to the “index” patient• All partners tested to establish prevalence of HIV
among partners
Del Romero J, BMJ 2010
9
Prevalence of HIV infection in the partners, at entry
No HAART HAART0123456789
10
44/476 0/149
Pe
rce
nt o
f pa
rten
airs
infe
cted
Del Romero J, BMJ 2010
10
Incidence of HIV infection in the partners, during follow-up
Treatment Couple-years New infections
No HAART 863 5
HAART 417 0
Del Romero J, BMJ 2010
11
Condoms plus HAART in comparison to condoms alone: 3 African studies
What they had in common:• Sero-discordant heterosexual couples• Condom promotion
How they differed:• Study A*, without HAART• Study B**, with HAART• Study C***, a period without HAART followed by a
period with HAART
* Wawer M et al. Lancet 2009** Bunnell R et al. Abstract 29, 15th CROI, Boston 2008; AIDS 2006***Donnell D, Lancet 2010
12
Results
Study A* Study B** Study C***« before » « after »
Condoms HAART - -
Infections %/year 12 0.5 2.23 0.39
* Wawer M et al. Lancet 2009; 374:229-37 ** Bunnell R et al. Abstract 29, 15th CROI, 2009*** Donnell D, Lancet 2010
13
In conclusion
Circumstantial evidence indicates that:• HAART lowers MTCT• HAART lowers heterosexual transmission• HAART appears more efficacious than condoms
(or has a marked additional effect when used in combination with condoms), in sero-discordant heterosexual couples
14
What has been the effect of ART on the AIDS epidemic ?
• Introduction of ART, 1990-2000• Expansion of ART, 2000-2010
15
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00
20
01
0
500
1000
1500
2000
2500
Bull. OFSP 2001
Newly Diagnosed HIV Infections in Switzerland
AZT HAART
16Montaner J, CROI 2010
1996
1997
1998
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2000
2001
2002
2003
2004
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2006
2007
2008
2009
0
100
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0
1000
2000
3000
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6000
Newly Diagnosed HIV Infections, and N of pts on HAART in B.C., Canada
17
Amsterdam, MSMsNew infections per seropositive individual If > 1, the epidemic grows, if < 1, it shrinks.
1985 1994 1996 2002 20020
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
1.7
0.9 0.81.1
1.5
Theoretical R(t) in 2002, without HAART, but with the 2002 sexual behavior
Bezemer D et al., CROI 2001, AIDS 2008
R(t)
18
Conclusions
• Introduction of ARVs in the 1990ies coincided with a decrease in new HIV infections
• Other things being equal, without HAART, new infections might have been 50 to a 100 percent more frequent by 2000
19Montaner J, CROI 2010
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
0
100
200
300
400
500
600
700
800
0
1000
2000
3000
4000
5000
6000
Newly Diagnosed HIV Infections, and N of pts on HAART in B.C., Canada
IDUs only
20
Swiss HIV Cohort: More patients with stably suppressed viral load
0%
20%
40%
60%
80%
100%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Perc
ent o
f par
ticip
ants
Stably suppressed Improving Unstable Always detectable
Adapted from Ledergerber et al. CROI 2010
21
More patients are treated, and less are infectious (VL > 500, pink)
> 500
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
< 500
22
2002
2003
2004
2005
2006
2007
2008
2009
0
2
4
6
8
10
12
600
800
1000
1200
1400
1600
1800
Swiss Cohort: N of pts with viremia > 500
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2002
2003
2004
2005
2006
2007
2008
2009
0100200300400500600700800900
1000
0
200
400
600
800
1000
1200
1400
1600
1800
Theory: What you would expect
The number of potentiallyinfectious persons starts to fall..
..and after a lag of a few yearsnewly discovered infections
decline in parallel
24
2002
2003
2004
2005
2006
2007
2008
2009
0
100
200
300
400
500
600
700
800
900
600
800
1000
1200
1400
1600
1800
Switzerland: Newly Diagnosed HIV Infections, and N of pts with viremia > 500 in the SHCS*
* SHCS = Swiss HIV Cohort Study
25
Conclusions (2000 to 2010)
1)Expansion of treatment, and better efficacy, diminished the pool of potentially infectious persons
2)The number of newly discovered infections, after years of stability or even increase, may be declining again
2626
What would happen to the epidemic if even more infected
persons were treated?
Montaner, Hogg et al. Unpublished, 2006
Treat all
Treat 30%
0123456789
10
200620102014201820222026203020342038
HIV
infe
cti
on
s p
er
10
00
p
op
ula
tio
n
2006 10 14 18 22 26 30 34 38 42 2050
Projections for British Columbia
0
5
10
15
20
25
30
2006 2010 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050
Year
Co
st (
bill
ion
s)
Treat all Treat 30%
Costs of treatment
Treat allTreat 30%
2006 10 14 18 22 26 30 34 38 42 2050
109 $
Hogg et al. Unpublished, 2006
0
5
10
15
20
25
30
2006 2010 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050
Year
Co
st (
bill
ion
s)
Treat all Treat 30%
Costs of HAART
2006 10 14 18 22 26 30 34 38 42 2050
Billions de $
Small investmentGreat
savings
Lima VD et al. JID 2008Hogg et al. Unpublished, 2006
30
If Lima and Montaner are right, it is enough to treat > 75% of those with CD4 counts < 350, and after a while, there will be close to zero new infections: HIV will disappear (Lima et al. JID, 2008)
Treatmen
t coverag
e
50 %
75 %
90 %
100 %
31
2000 2020 2040
ARV for CD4 < 350
Granich et al. 2008
But if Granich and Williams are right, HIV will never be defeated by treating only those with CD4 counts below 350. One needs to test the whole population frequently, and treat all those found to be infected (green curve)
32
All models are wrong, but some are useful…
Box, G.E.P., Robustness in the strategy of scientific model building, in Robustness in Statistics, R.L. Launer and G.N. Wilkinson, Editors. 1979,
Academic Press: New York.
33Blower et al., Science 2000
Percent of Cases Treated
50% 60% 70% 80% 90%
100100
80
60
40
20
0
-20
-40
-60
-80
-100
-120Pe
rce
nt o
f New
Infe
ctio
ns P
reve
nte
d
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50% 60% 70% 80% 90%
100
80
60
40
20
0
-20
-40
-60
-80
-100
-120Pe
rce
nt o
f New
Infe
ctio
ns P
reve
nte
d
Depending on assumptions regarding risk behaviourand selection of drug resistance, at 70% of patients treated, the effect on
new infections could range from 40% prevented to doubled
35Kahn JG et al. 17th CROI, 2010, abstract 965
• Compared to treating only patients with less than 350 CD4 cells, universal ART would reduce costs by 4.9 billion US$ …
• « I therefore believe that you have substantially underestimated, and deliberately misrepresented, the costs of your proposed elimination strategy »
36
Let’s declare a model armistice, and instead get
some data !
Dabis, Newell, Hirschel, Lancet 2010
37
HPTN* 052
• Myron Cohen et al.: Randomised study to evaluate HAART in preventing sexual transmission in sero-discordant couples
* HPTN: Health Prevention and Treatment Network
38
Inclusion Criteria
• 1750 couples (3500 individuals), fully recruited• CD4 = 350-550 cells/mm3• One partner HIV+, the other HIV-• Endogamous: 93% say that they had only one
sex partner during the last six months.
39
Randomisation
• In the intervention group, ART starts right away, i.e. at a CD4 level between 350 and 550
• In the control group, according to local indication (CD4 = 200 to 250, rising more recently to 350)
40
Endpoints
1. Transmissions
2. Sustainability, with a planned follow-up of 5+ years
Results expected in 2015
41
Limitations of HPTN052
• Stable serodiscordant heterosexual couples are only part of the problem
• In the general population individual randomisation is not feasible, because it would necessitate tracking and testing of all sex partners
42
• Measure the incidence of HIV before and after introduction of ART, or before and after expansion of ART
• Examples: British Columbia (J. Montaner et al.), San Francisco, Switzerland
General population:The before-and-after approach
43
2002
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2006
2007
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0
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600
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600
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1200
1400
1600
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Switzerland: Newly Diagnosed HIV Infections, and N of pts with viremia > 500 in the SHCS*
* SHCS = Swiss HIV Cohort Study
44
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
0
50
100
150
200
250
300
350
400
0
100
200
300
400
500
600
700
800
900
Newly Diagnosed HIV Infections, andN of MSMs with viremia > 500 in the SHCS*
MSMs
* SHCS = Swiss HIV Cohort Study
45
February to June 2008: A campaign to eliminate acute HIV infections in MSMs in
Switzerland
46
Problems with the before-and-after approach
1. Not all evidence goes into the same direction
2. B after A B because of A(If HIV incidence falls after expansion of ART, it is not certain that the expansion caused the fall)
47
• « Children whose mothers listenend to Mozart during pregnancy are more intelligent »
• « The H1N1 vaccine has caused my multiple sclerosis because 5 days afterwards I started having double vision » (Tribune de Genève, 15 mars 2010)
The « post hoc ergo propter hoc » - fallacy is not new…
48
How To Do Better
• Compare two regions, at the same time:– Region 1: Test-and-Treat– Region 2: Continue as before
Measure, in both regions, the number of new HIV infections
• Better but not perfect: The two regions will differ in many respects:
– Number and type of sex partners– Use of condoms– Prevalence of circumcision– Age
49
… but if one compared not two, but thirty regions, 15 with expanded ART, 15 without, and each time, HIV incidence falls in the « Test-and-Treat » regions but
remains the same in the control regions …
50
This is the essential idea behind the methodology called « cluster-randomized
trial », where the unit of randomization is not the individual, but a community of individuals,
for instance a village
… but if one compared not two, but thirty regions, 15 with expanded ART, 15 without, and each time, HIV incidence falls in the « Test-and-Treat » regions but
remains the same in the control regions …
51
ANRS
• Working group (AC12, B. Hirschel, F. Dabis): Priorities 2010 – 2015: Treatment as prevention (TasP), or « Test-and-Treat (TnT) »
• Together with a partner in Africa
52
The Africa Center for Health and Population Studies
Durban
Johannisburg
Marie-Louise Newell
Ukuphila kwami, ukuphila kwethu* Test-and-Treat A cluster-randomized trial in Hlabisa, KwaZulu-Natal, South Africa
Francois Dabis and Marie-Louise Newell (PIs), Africa Centre and Hlabisa Department of Health collaborators
• Pilot Phase 2010 – 2013, Trial Phase 2013-2015• Approximate budget of 3’000’000 € for the Pilot Phase
only, with important downstream commitments• ANRS is « interested », and looking for additional
financing from other sources
* My Health for Your Health
54
Basic Plan• Screen « everybody »• 2 arms :
– Intervention Clusters: Treat all who screen HIV+– Control clusters: HIV+ with treatment indications
according to local guidelines, but using the type of HAART prescribed in the Intervention Clusters.
55
Endpoints
• Primary– Incident HIV infections, as measured by repetitive 6-
monthly screening• Secondary
– Acceptability and results of widespread testing– Behavioral modifications– Costs and cost-effectiveness– Morbidity and mortality in HIV+
• HIV related• « Non-HIV-related »• HAART-related• Test-and-Treat is also a «when-to-start » study
56
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Hurdles
1. Attrition
2. Harm (to the individual) versus benefit (to the community)
3. Cost and sustainability
58
Attrition…Intervention Group
• Not all will be tested• Of those who are tested,
some will not receive their results
• Of those who receive results and are HIV+, not all will be treated
• Of those who are treated, not all will have effective treatment
• Of those with effective treatment, not all will continue
59
Attrition…Intervention Group
• Not all will be tested• Of those who are tested,
some will not receive their results
• Of those who receive results and are HIV+, not all will be treated
• Of those who are treated, not all will have effective treatment
• Of those with effective treatment, not all will continue
Control Group• Some already on ART• Proportion on ART
expected to increase:– Expansion of access– Revision of indications (limit
of 350 CD4 cells instead of 200)
• Of those who remain off treatment, many will use other prevention methods:– Condoms– Microbicides– Circumcision
Attrition: Example from MTCT
Source: Stringer EM et al. AIDS 2003; 17:3077 (Lusaka, Zambia)
Preg
nan
t
Co
un
selled
Tested
Po
sitive
Mo
thers N
VP
Ch
ildren
NV
P
Partn
ers te...
0
10000
20000
30000
40000
17263
12065
2924 1654 1157 86
61
Harm versus Benefit
• Consider risks and benefits both to the individual, and the community
• Health benefits– Persons in intervention clusters will probably have less
HIV-related diseases. This will be a secondary endpoint in the trial
– Effect of tuberculosis could be particularly beneficial:• Occurs at higher CD4 counts• « Spill-over » into the HIV-negative population
62
Risks and beneftis (continued)
• Medical risks– Asymptomatic individuals with intact immune systems
may derive little or no benefit, and probable side effects, from HAART
• Non-medical risks– Without widespread acceptance, test-and-treat
programs cannot succeed– Test-and treat-programs must avoid undue pressure
on individuals to get tested and begin treatment– On the plus side, the perception that treated patients
are not longer infectious, may decrease stigma and discrimination
63
Resources and Sustainability
• If treatment has a preventive effect, it will increase pool of people potentially eligible for HAART– Will increase pressure for availability of ARVs– Will increase costs in the short run– Long-term sustainability and resistance is
certainly an issue. – Operational research would provide years of
follow-up and surveillance of infection, without randomisation
64
65
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67
Acknowledgements
• Africa Center: M.-L. Newell• S. Timberlake, J. Amon• ANRS: Brigitte Bazin, J.-F. Delfraissy, F. Dabis• J. Montaner• R. Granich• M. Cohen• Th. Wägli• A. Calmy, E. Boffi, J. Ambrosioni, C. Delhumeau• F. Schöni, N. Low, B. Althaus, M. Egger, O. Keiser• B. Vidondo, M. Gebhart
68
Spare Slides
69
N on HAART And Newly Diagnosed Infections in Switzerland, 2003-2009
2003 2004 2005 2006 2007 2008 20090
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Why this marked decreasefrom 2008 to 2009 ? New drugs with less resistance?
New infections
N treated
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N on HAART And Newly Diagnosed Infections in Switzerland, 2003-2009
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N on HAART And Newly Diagnosed Infections in Switzerland, 2003-2009
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Attrition: Example from MTCT
• Pregnant women 40000• Received counseling 17263 40000 43%• Tested 12438 40000 31%• Received test results 12065 40000 30%• Positive 2924 9403 30%• Received nevirapine
– Mothers 1654 940318%
– Children 1157 940312%
• Partners tested 86 9403 0.9%
Observed Ideal Obs/Ideal
Source: Stringer EM et al. AIDS 2003; 17:3077 (Lusaka, Zambia)
73
Newell et al.
• 32 districts
• 16 with, 16 without intervention
• Approx. 40000 persons
74
Risk Compensation
• Increased sexual risk taking in intervention clusters– May, or may not matter while patients are on HAART– Has to be considered in the local context (where
infection rates at times have been shockingly high even in trial settings with condom promotion)
– Some reassurance provided by the circumcision trials, where there was no increase in sexual risk taking in intervention groups
75
Follow-up
Test-and-Treat 1: Years 1 and 2:
Evaluation
Test-and-Treat 2: Years 3 to 5 (to 10?)
76
TnT1 compared to TnT2
TnT1 TnT2Focus onefficacy sustainability
Randomisation unit Cluster No randomisation
Indication for HAARTin intervention group All HIV+ All HIV+
Indication for HAARTin control group usual care No control group
Follow-up 2 years 3-8 years
77
N o
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N on HAART increases in Switzerland
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Newly Diagnosed HIV Infections, andN of pts with > 500 in Switzerland
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01002003004005006007008009001000
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Newly Diagnosed HIV Infections, andN of pts with viremia > 500 in Switzerland
Heterosexuals
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