HAART as prevention - WHO2008. 8. 9. · Viral Load ART 250 1200 1000 800 600 400 200 Viral Load...
Transcript of HAART as prevention - WHO2008. 8. 9. · Viral Load ART 250 1200 1000 800 600 400 200 Viral Load...
HAART as Prevention
Reuben GranichHIV/AIDS Department
World Health Organization
5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa
21 July 2009
Smallpox eradication 1796 to 1977:Edward Jenner to Merca Town, Somalia
Outline:
• Background
• Treatment of persons already living with HIV
• Universal voluntary HIV testing and immediate ART model
• Conclusions
2005 and 2009 G8: Universal Access
2005 G8 Summit at Gleneagles, Final Communiqué:“…working with WHO, UNAIDS and other international bodies to develop and implement a package of HIV prevention, treatment and care, with the aim of as close as possible to universal access to treatment for all those who need it by 2010.”
2009 G8 Summit at L'Aquila, Final Communiqué:We have made progress towards universal access…in the current global
crisis we reaffirm our commitment to address the most vulnerable.
Unprecedented investment faces most serious economic crisis since 1930's
$11.3
$8.8$7.9$6.1
$5.0$3.2
$1.6$1.4
$13.8
0
10
20
30
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
USD
bill
ion
Resources Available for HIV services
Resource needs for country defined UA
Resource needs
Available resources
Towards universal treatment access
Year New patients on ART each year
Cumulative patients ever started on ART
2005 25,000 37,8402006 35,000 70,0002007 40,000 110,0002008 45,000 155,0002009 45,000 --
Malawi: scale-up against formidable odds
Mind the prevention gap…..
End 2007:• 3 million were receiving ART
--about 1 million people added• 6.7 million in need• 2.7 million new infections
Estimated treatment gap in low- and middle-income countries
2002-2007
1 000 000 2 000 000 3 000 000 4 000 000 5 000 000 6 000 000 7 000 000 8 000 000 9 000 000
10 000 000
2003 2004 2005 2006 2007
Peop
le
95%
69%
Estimated gap: <200 CD4 but not on ART
On ART
Antiretroviral therapy - an entitlement program?
"As a result, taxpayers are accumulating an indefinite—and indefinitely growing—responsibility for keeping people alive. Somehow, somebody has to work out how to stop the disease spreading".
The Economist, 9 August, 2008
Combination preventionMultiple disciplines and approaches
Community Interventions
Biomedical Interventions
Structural Interventions
HIV testing and linkage
to care
Individual and small
group behavioral
interventions
HIV prevention
Adapted from Coates T
Efficacy trials of biomedical interventions for HIV sexual transmission, 2009
Adapted from Cohen J, Science 2008
Intervention Completed Efficacious
Male circumcision 3 3
STI treatment 5 1
HSV-2 suppression 2 0
Cervical barriers 1 0
Microbicides 9 0
HIV vaccines 4 0
TOTAL 24 4
Evidence supports ART for prevention of HIV transmission
• Transmission only occurs from persons with HIV• Viral load is single greatest risk factor for HIV transmission• ART can lower viral load to undetectable levels• PMTCT proof of concept of ART reducing transmission• Observational evidence in heterosexual couples • Previous modelling work suggests considerable potential• Knowing one's HIV status is key to ART for prevention• When to start ART is not known with certainty
HIV treatment reduces viral load and heterosexual transmission
Quinn et al. NEJM. 2009;342(13):921-929.
HIV sexual transmissibility meta-analysis:No transmission on ART below 400 copies/ml
Attia S, et al.AIDS 2009 Jul 17;23(11):1397-404.
CDC HIV Testing Recs
PACTG 076 & USPHS ZDV Recs
Community studies suggestpopulation-level impact of ART
Free ART
TaiwanBritish Columbia, Canada
Wood et al. BMJ 2009;338b:1649
Fang et al. JAIDS 2004;190:879-85
Late initiation of ART and mortality
Source: Egger M, CROI 2007
When to start ART….or how late is too late?
• 17,517 patients from US and Canada (1996-2005)
• 69% increase in mortality for those who started treatment below CD4+ <350/cu mm
• 94% increase in mortality for those who started treatment below CD4+ <500/cu mm
Kitahata MM et al. N Engl J Med 2009 Apr 30;360(18):1815-26.Sax PE et al.N Engl J Med 2009 Apr 30;360(18):1897-9.
When to Start Consortium: analysis of 18 cohorts suggests that earlier start improves outcome
When to start consortium.Lancet 2009 Apr 18;373(9672):1352-63
Randomized controlled trial of earlier versus deferred ART in Haiti
CIPRA HT 001
Start ART at CD4+ <350/cu mm, compared to AIDS or CD4+ <200/cu mm
• 816 patients • First line regimen: AZT, 3TC, EFV• 23 deaths in deferred group, 6 in early
treatment group (p<.001)• 36 vs. 18 cases of TB in deferred vs early
treatment group (p<.013)• DSMB recommended immediate end of trial
Pape J, Fitzgerald D et al, 2009
•HIV may be associated with serious non-AIDS defining events
•Cardiovascular•Renal•Liver•Non-AIDS malignancies
•At higher CD4 counts non-AIDS events are much more common than AIDS events
•Does ART use reduce risk of some serious non-AIDS events?
SMART Study Group, NEJM 2006 & Neaton et al, Current Opinion in HIV/AIDS 2008Slide courtesy of A Phillips
Risk of non-AIDS morbidity and mortality
1 2
Renal
Liver
All serious non-AIDS
CVD
Non-AIDS malignancy
0.5 3 5 10
Other non-AIDS death
Hazard RatioIntermittent vs. continuous ART
SMART Trial
Havlir, Getahun et al. 2008 JAMA 300(4):423-430
CD4 level is associated with TB incidence:earlier start may decrease TB risk
"TB death zone"
Slide adapted by Dr. Abhishek Sharma
CD4 cell count over the course of untreated HIV-1 infection in adults
Korenromp EL, et al. PLoS One 2009;4(6):e5950.
When to start ART?A matter of perspective
years
1200
1000
800
600
400
200
HIV infection ART 500
CD4 Count
Viral Load
ART 250
1200
1000
800
600
400
200Viral Load
ART 500 ART 250
years
2-4 years earlier now appears like a short period
CD4 Count
2-4 years earlier significant period
Slide adapted from Julio Montaner
Key characteristics of current US, European and WHO ART guidelines
Guidelines When to Start in asymptomatic patients(preferred approach)
Preferred initial ARV therapy
Preferred subsequent ARV therapy
Preferred treatment failure/switching criteria
DHHS (2008) CD4 <350 (stronger if < 200)
2NRTI (TDF/FTC) + NNRTI (EFV) or bPI (ATV/r or DRV/r or FPV/r or LPV/r)
Guided by resistance testing/tropism testing
VL + CD4 (no consensus on thresholds)
IAS (2008)
CD4 < 350 (consider if > 350 in some situations) Consider if high viral replication, rapid CD4 decline, prevent transmission, other Dz.
2NRTI (ABC/3TC or TDF/FTC) + NNRTI (EFV) or bPI (ATV/r or DRV/r or FPV/r or LPV/r or SQV/r
Guided by resistance/tropism testing
VL> 500-1000
EACS (2008)
CD4 < 350 (consider if > 350 in some situations)
2NRTI (ABC/3TC or TDF/FTC) + NNRTI (NVP or EFV) or bPI (FPV/r or LPV/r or SQV/r)
Guided by resistance testing
VL > 500-1000
BHIVA (2008)
CD4 < 350 (consider if > 350 in some situations)
2NRTI (TDF/FTC) + NNRTI (EFV)
Guided by resistance testing
VL > 400
WHO EURO (2007/2008)
CD4 between 200-350 2NRTI (ABC/3TC or AZT/3TC or TDF/XTC) + NNRTI (EFV)
2 NRTI (ABC/ddI or TDF/XTC or AZT/3TC or TDF/ABC or AZT/ddI) + bPI (LPV/r)
VL > 400 (early failure) VL > 1000-10,000 or 25% reduction in CD4 (late failure)
WHO Global (2006)
CD4 < 200(consider between 200-350 but start before reach 200)
2NRTI (AZT/3TC or TDF/XTC) + NNRTI (NVP or EFV)
2 NRTI (ABC/ddI or TDF/XTC or AZT/3TC) + bPI (ATV/r or LPV/r )
Clinical + CD4 (if available VL > 10,000)
Slide from Vitoria M, 2008
Coverage of ART among eligible people living with HIV
Kenya (2007 KAIS)
HIV test
57% Unaware of status, not
on ART
4% know status, not on ART
39% know status, on ART
Among those who knew status and were eligible 92% were on ARTMohammed, CROI 2009
57%
39%
Counseling and testing is feasible and works in a wide variety of settings
Photos courtesy of Bunnell R, Marum E, and Vestergaard Frandsen
"Essentially, all models are wrong, but some are useful."
– George E. P. Box
•Southern-African type epidemic•Data from SA, Uganda, Malawi and elsewhere
•Initial doubling time in South Africa ≈ 1.25 years•Each person infects one other person every 1.25 years.
•Life expectancy after infection ≈ 10 years
•Each HIV positive person infects 10/1.5 ≈ 7 people
•Cutting transmission by a factor of more than 8 would eliminate HIV infection (R0<1)
Approach to estimating R0
Infectivity varies through the course of infection
0
2
4
6
8
10
0 2 4 6 8 10Years
Rel
ativ
e in
fect
ious
ness
Acute phase
Chronic phase
Finalphase
Granich RM et al. Lancet 2009 Jan 3;373(9657):48-57.
Relationship between HIV testing frequency, CD4 count, and R0
R0<1
Program implementation
0.0
0.2
0.4
0.6
0.8
1.0
2000 2010 2020
Years
Pro
porti
on o
f tot
al
0.0000.0050.0100.0150.020
1980 2000 2020 2040
Inci
denc
e/ye
ar
0.0000.0010.0020.0030.0040.005
1980 2000 2020 2040
No ART<350Universal
0.00
0.05
0.10
0.15
1980 2000 2020 2040
Prev
alen
ce
0.00
0.05
0.10
0.15
1980 2000 2020 2040
0.000
0.005
0.010
1980 2000 2020 2040
Mor
talit
y/ye
ar
0.000
0.005
0.010
1980 2000 2020 2040
HIV ART
HIV and ART incidence, prevalence and mortality,1980-2040
Prop
ortio
n of
ado
lesc
ents
and
adu
lts 1
5 ye
ars
or o
lder
Strategy
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 2040 20500.00
0.01
0.02
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 2040 20500.00
0.01
0.02
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 2040 20500.00
0.01
0.02
0.00
0.05
0.10
0.15
1980 1990 2000 2010 2020 2030 2040 20500.00
0.01
0.02
Current phase Roll out Elimination
PrevalenceIncidenceMortality
On ART
Estimated number of AIDS-related deaths for 2008 to 2050
Strategy Deaths Deaths averted
Neither strategy 11,078,000 --
ART started <350 8,658,000 2,419,000
ART started <350 + universal voluntary HIV testing/immediate ART
3,879,000 7,199,000
ART started <350 + universal voluntary HIV testing/immediate ART + other prevention strategies
3,727,000 7,350,000
0
2
4
6
8
2 0 0 0 2 0 1 0 2 0 2 0 2 0 3 0 2 0 4 0 2 0 5 0Y e a r
US
$ bi
llion
s/ye
ar
.
Blue: 17% global funding (UNAIDS)Brown: 17% projected funding (UNAIDS)Green: Universal testing + immediate ARTRed: <350 with universal voluntary testing
Annual cost savings
Estimated and projected funding and costs: We appear to be in the right ball park….
Cohen J. HIV/AIDS. The great funding surge. Science 2008 Jul 25;321(5888):512-9.UNAIDS. Financial resources required to achieve universal access to HIV prevention, treatment, care and support. UNAIDS Report (2007). http://data.unaids.org/pub/Report/2007/20070925_advocacy_grne2_en.pdf.
Conclusions from modeling exercise
• Universal voluntary HIV testing and immediate ART combined with other prevention interventions:
• 95% reduction in new HIV cases in 10 years• Incidence reduced from 15-20,000 to 1000 per
million• Prevalence or the number of people living with HIV
becomes less than 1% by 2050• Initial resources would be higher but over time, given
the reduction in HIV incidence, this approach may provide cost savings
• Estimated costs are within UNAIDS estimates for Universal Access for a population this size.
• Theoretical model
WHO next steps
Consultation on ART as prevention (Nov 2009)• Researchers (clinical, socio-behavioural,
prevention & modellers)• NGOs, civil society & people living with HIV• Ethicists & human rights experts• Health economists, donors, research funding
agencies• Affected country representatives• UNAIDS Co-sponsors and WHO HQ and
Regional staffFocus
• Explore human rights and ethical implications
• Clarify research priorities• Explore feasibility and acceptability
Public health is purchasable. Within a few natural and important limitations any community can determine its own health.
--Hermann M. Biggs(29 Sep 1859 - 28 Jun 1923)New York City's Public Health Officer and public health pioneer
Jonathan MerminJulio Montaner Jung-Der Wang Navneet GargMarco Vitoria Miriam Sabin Mona Sfeir Nicole Schiegg Paula Akugizibwe Pedro Kahn Rebecca Bunnell Richard Skolnik Robin WoodRod Bennett Siobhan Crowley Steve Lawn Susan Allen Teguest Guerma Tim Mastro Travis Porco Ying-ru Lo Yves Souteyrand International AIDS SocietyWHO staffPEPFAR staff
Thank you!Brian Williams (Senior author)Charles Gilks Christopher DyeKevin De CockA.D. Harries Alexandra CalmyAndrew BallAndrew Phillips Brad Hersh Caroline Ryan Celicia SerenataCharles Holmes Chi-Tai FangColleen Daniels Craig McClure Diane Bennett Diane HavlirEleanor Gouws Elizabeth MarumEric Schouten Francois Venter Haileyesus GetahunJim KahnJohn Stover