Post on 30-Mar-2015
Antiretroviral Therapy:An HIV Prevention Strategy?
Wafaa El-Sadr, MD, MPHColumbia University
Harlem HospitalNew York
Persons Living with HIV/AIDS 200833.2 million (30.6-36.1 million) worldwide
Latin AmericaLatin America1.6 million1.6 million
E. Europe/Central AsiaE. Europe/Central Asia1.6 million1.6 million
E. Asia/PacificE. Asia/Pacific800,000800,000
Sub-Saharan AfricaSub-Saharan Africa22.5 million22.5 million
N. Africa/Mid-EastN. Africa/Mid-East380,000380,000 South/S.E. AsiaSouth/S.E. Asia
4.0 million4.0 millionCaribbeanCaribbean230,000230,000
Source: UNAIDS, AIDS Epidemic Update, December 2009
North AmericaNorth America1.3 million1.3 million
OceanaOceana75,00075,000
Western & Central Europe
760,000760,000
Use of ART for PMTCT
HIV RNA Levels Associated with HIV Transmission Risk
0
5
10
15
20
25
30
Viral load (HIV-1 RNA copies/ml) and HIV transmission
Tran
smis
sion
rate
per
100
Per
son-
Year
s
<400
400-
3499
3500
-999
9
10 0
00-4
9 99
9
>50
000
Quinn TC, et al. NEJM 2000; Fideli U, et al. AIDS Res Hum Retrovir 2001
<400
400-
3499
3500
-999
9
10 0
00-4
9 99
9
>50
000
<400
400-
3499
3500
-999
9
10 0
00-4
9 99
9
>50
000
All subjectsMale-to-Female
TransmissionFemale-to-Male
Transmission
Impact of Antiretroviral Therapy (ART)on HIV Transmission
• Prospective cohort study of home-based ART in a rural community in Uganda (n=926)
• After starting ART– Median HIV RNA levels decreased from 122,500
to <50 copies/mL– Estimated HIV transmission rate reduced by 98%
• From 46 to 1 per 1000 PY– Risky sex decreased by 70% (P=0.002)
Bunnell R, et al. AIDS. 2006;20(1):85
Impact of ART on HIV Transmission
• HIV discordant couples (Rwanda and Zambia) (n= 2,993 discordant couples)• HIV+ persons with CD4 <200 cells/mm3on ART• HIV incidence by partner ART status:
– Not on ART: 3.4 / 100 PY– On ART: 0.7 / 100 PY
• OR, 0.2; 95% CI, 0.08-0.6
Sullivan P, et al. CROI Montreal. 2009
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.
Antiretroviral Treatment as Prevention
• Anema A, et al. The use of HAART to reduce HIV incidence at the population level. CMAJ 2008; 179:13-4.
• Bateman C. Treat all HIV-positive people--and bury the pandemic in 14 years. S Afr Med J 2009; 99:80-2.
• Montaner JS, et al. The case for expanding access to HAART to curb the growth of the HIV epidemic. Lancet 2006;368:531-6.
• DeGruttola V, et al. Controlling the HIV epidemic, without a vaccine! AIDS 2008; 22:2554-5.
• Dieffenbach CW, Fauci AS. Universal VCT and ART for prevention of HIV transmission. JAMA 2009; 301:2380-2
Lancet 2009; 373:48-57
Modeling of Test and Treat
Model Assumptions
• High uptake of annual testing by all >15 year old individuals
• All HIV+ individuals start ART immediately, irrespective of stage of HIV disease
• 99% decrease in infectiousness• High adherence with ART• Low failure with first line ART
Estimated number of new HIV infections by transmission category, 1977-2006
MSM
IDU
HET
*50 States and District of Columbia
Courtesy of Kevin Fenton, CDC
HIV Prevalence for Selected Countries in Sub Saharan Africa and Subpopulations in the United States
Test and Treat
Test
Adoption of saferbehaviors by HIV+ persons
Treat with ART
Maintain viral suppression
Decrease in HIV Transmission
+
HPTN TNT-Plus Study Concept
Test
HIV Positive
Adopt safer behaviors
Enroll in Care
Treat with ART
Maintain viral suppression
Decrease in HIV Transmission
Positive Prevention
Increase in Testing
Initiationof ART
Linkage to care
sites
Support of adherence
Testing
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%
Percentage HIV TestedCountry % Tested in preceding 12 months
Woman MenCongo 6.5 4.8Cote d’Ivoire 3.7 3.2Ethiopia 2.3 2.3Namibia 10.6 17.6Rwanda 12.0 11.0Swaziland 21.9 8.9Uganda 12.0 10.4Zambia 18.5 11.7Zimbabwe 7.0 7.0United States 10%
20
668 692666
780842
992
646
43.3%
46.0%
54.0%
69.7%
30.3%
67.7%
32.3%
62.2%
37.8%
62.9%56.7%
37.1%
66.1%
33.9%
New AIDS Cases and “Late Testers”Persons newly diagnosed with AIDS, and
proportion first diagnosed with HIV within 12 months, 2001-2006 (N=4,640)
Late Diagnosis of HIV• NYC: 27% of persons newly diagnosed with HIV had
concurrent diagnosis of AIDS in 2005• First CD4+ count performed within 12 months after HIV test
– CD4+<200: 31.7%– CD4+ 200-350: 8.2%– CD4+ 351-500: 6.9%– CD4+ >500: 8.8%– Missing: 44%
• Concurrent HIV/AIDS diagnosis (1 month)– More than twice risk of death within 4 months
HR: 2.27 (95% CI 1.94-2.65)
NYC DOHMH surveillance 2007Hanna et al 2008
Positive Prevention
Positive Prevention InterventionsIntervention Name
Healthy Relationship
CLEAR WILLOW SUMITEnhanced Peer-Led
Options
Study Size 328 175 366 811 497
Setting Community AIDS Service Organization
Community agency, residence or community site
Study site and HIV service clinic
Study site HIV care clinic
Unit of Delivery
Group Individual Group Group Individual
Deliverer Male and female community facilitators
Licensed therapist or social worker
HIV+ peer educators and health educators
HIV+ MSM peer facilitators
HIV physicians
Outcome Measure
UAI, UVI, AI, VI, with non-HIV+ partners: condom use
Condom Use UVI; condom use; STI
UAR with non HIV+ partner
UAI, UVI, UAR, UVR, UIO
Linkage to Care
25
Time from HIV Diagnosis to Care Entry*
1,340 1,827 1,635 1,502 1,342 1,510
50%
Factors Associated with Delayed Initiation of Care
• Of 1,928 patients, – 1,228 (63.7%) initiated care within 3 months of HIV
diagnosis– 369 (19.1%) initiated care >3 months– 331 (17.2%) never initiated care
• Predictors of delayed initiation of care:– Diagnosis at community testing site (HR: 1.9, 95%CI 1.5-2.3)– Diagnosis in corrections, STI or TB clinic (HR:1.3, 95% CI; 1.1-1.6)
– Non-white race/ethnicity (HR: 1.8; 95% CI 1.5-2.0)
– Injection drug use (HR: 1.3; 95% CI1.1-1.5)– Foreign born (HR: 1.1; 95% CI 1.0-1.2)
Torian et al 2008
Treatment with ART
When to Start Antiretroviral Therapy
LaterEarlier
Early versus Later ART
Possible Benefits Possible Risks
Later ART initiation • Lower medication and monitoring costs• Lower incidence of long term drug toxicity• Decrease in development of resistance
• Lower preservation of immune function• Increased risk of disease progression• Risk of HIV transmission prior to ART initiation
Earlier ART initiation • Improved preservation of immune function• Prolonged disease-free survival• Decreased HIV transmission rates
• Increased medication and monitoring costs• Increased incidence of long term drug toxicities• Increased development of drug resistant HIV
INSIGHT START Study HIV-infected individuals who are ART-naïve with
CD4+ count > 500 cells/mm3
Early ART GroupInitiate ART immediately following randomization
N=2,000 fordefinitive trial
Deferred ART GroupDefer ART until the CD4+ count declines to < 350 cells/mm3 or
AIDS developsN=2,000 for
definitive trial
Serious AIDS, Non-AIDS Events or Death
HPTN 052
HIV-infected subjects with HIV-infected subjects with CD4 350 to 550cells/CD4 350 to 550cells/µL with discordant partnerµL with discordant partner
Immediate ARTImmediate ART350-550cells/uL350-550cells/uL
Deferred ART Deferred ART CD4 <250>200CD4 <250>200AZT+3TC+EFVAZT+3TC+EFV
Endpoints: i) HIV Transmission to partners Endpoints: i) HIV Transmission to partners ii) OIs and clinical Eventsii) OIs and clinical Events iii) ART toxicityiii) ART toxicity
Randomization
Thailand, South Africa, Botswana, Thailand, South Africa, Botswana, Kenya, Malawi, Brazil, India Kenya, Malawi, Brazil, India
Other Modelling--- All treated
Relative infectivity 0.01
Dropout: 1.5% /year
14% prevalence in population
--- ART: 65% symptomatic
20% asympotmatic
Relative infectivity 0.03
Dropout: 5% symptomatic
20% asymptomatic
Elimination theoretically possible
--- ART: 65% symptomatic
no ART asymptomatic
Treated individuals noninfectious
Dropout: 5%/yr
HIV remains endemic at 34% prevalence and 2%/yr incidence
Wagner and Blower, Nature Proceedings, 2009
Adherence
Adherence to Antiretroviral Treatment
*p<0.01 for difference between months 1 & 4 and months 1 & 8
Mannheimer et al, FIRST Study CPCRA, 2000.
Percent reporting
100% adherence
HPTN 065 TLC-Plus Study“Testing Linkage to Care Plus
Treatment”PURPOSE
To evaluate the feasibility of an enhanced community-level HIV test, link-to-care plus
treat strategy in the U.S.
Study Components
I. TestingII. Linkage to careIII. Viral suppressionIV. Positive preventionV. Patient and provider survey
Study Communities
• Intervention communities– Washington DC– Bronx, NY
• Comparison communities– Houston– Philadelphia– Chicago– Miami
HIV Testing in NYC: The Bronx Knows
•Bronx with excess AIDS-related deaths (32% vs. 17% NYC pop.)•1 in 4 diagnosed with HIV & AIDS concurrently in the Bronx
Test all Bronx residents ages 18-64 yrs who have never been tested before to identify undiagnosed HIV+ persons
Link all HIV+ persons to high quality care and supportive services
“The Bronx Knows” Initiative
Washington, D.C.: 7 of 8 wards with 1.7-2.8% prevalence
0.0 - 0.60.7 - 1.21.3 - 1.81.9 - 2.42.5 - 3.0
Population Prevalence
REF: Shannon Hader. CROI 2009. Abst.57
City-wide by race/ethnicity and sex-----------------WF 0.2%HF 0.7%BF 2.6%WM 2.6%HM 3.0%BM 6.5%
4141
HIV Rapid Testing Expansion in DC
68.4% increase in number of tests done in 1 yr
N=43,271 N=72,864
97% of new HIV positives were identified in clinical settings
94% of new HIV positives were identified in clinical settings
Study ComponentsI. Expanded HIV Testing
This includes
1- social mobilization, with targeted messaging to promote testing
43
2- universal offer of HIV testing in emergency departments (EDs) and hospital inpatient admissions
Jul-
05
Sep
-05
No
v-05
Jan
-06
Mar
-06
May
-06
Jul-
06
Sep
-06
No
v-06
Jan
-07
Mar
-07
May
-07
Jul-
07
Sep
-07
No
v-07
Jan
-08
Mar
-08
May
-08
OP
New
Dx
IP N
ew D
x
ED
New
Dx
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
OP New Dx IP New Dx ED New Dx
Study ComponentsII. Linkage to Care
This component involves:
– test site randomization (20 per community)
– determine feasibility and effectiveness of» financial incentives vs.» standard of care (SOC)
Outcome: Proportion of newly identified HIV+ patients from HIV test sites who complete two clinical visits at HIV care sites
Study Components III. Viral Suppression
This component involves:
– care site randomization (20 per community)
– determine feasibility and effectiveness of» financial incentives vs.» standard of care (SOC)
Outcome: Proportion of patients at HIV care site achieving and maintaining viral suppression
Financial Incentives
• 2-arm RCT: • Information about
programs• Incentives worth up
to $750 for program completion, short-term cessation, long-term cessation
• Eligibility for incentives tied to quitting within first 6 months of enrollment p-value for difference < 0.0001
Volpp, Troxel, Pauly et al, New England Journal of Medicine. 2009; 360(7): 699-709.
Study ComponentsIV. Prevention for Positives
This involves:
– individual randomization of patients (6 care sites per community)
–determine effectiveness in decreasing risk behaviors
»computer-delivered intervention vs.»standard of care (SOC)
Study ComponentsPrevention for Positives
The computer-delivered intervention is:
–A modification of the Computer Assessment and Risk Reduction Education for HIV-positives (CARE+) platform, integrated with an audio-narrated self-interview (ACASI)
Study ComponentsV. Patient and Provider Surveys
These surveys aim to determine:
–knowledge, attitudes and practices regarding early initiation of ART
–knowledge and attitudes regarding financial incentives for linkage to care and viral suppression
Study Objectives and Outcomes
• Assesses feasibility and effectiveness outcomes, dependent on study component
• Assesses the feasibility of using surveillance data for outcomes
• All aim at determining feasibility of overall strategy
• TLC-Plus is not designed to measure a change in HIV incidence
Unique Features of TLC-Plus
• Partnerships – Between NIH and CDC– Across NIH institutes– With departments of health in major cities– With diverse stakeholders in communities
• Community (rather than research site) focus• Combine feasibility and effectiveness outcomes• Use of routine HIV surveillance data for key outcomes• Galvanize community support for expanded testing, care and
treatment
Conclusions• HIV prevention successes have been limited• Intense interest in use of antiretroviral therapy as a prevention
strategy• Success will require:
– effective implementation of multiple interrelated interventions at a broad community level
– Simple easy to measure outcomes at a community level• TLC-Plus Study will examine several strategies for:
– HIV testing– Linkage from testing to care– Enhanced and maintained viral suppression with ART– Positive prevention intervention
• Lessons learned may help inform larger definitive study of this strategy in the US and internationally
Acknowledgement
CDC: Bernard Branson, Kate Buchacz, Irene HallNYC DOHMH: Blayne Cutler and Lucia TorianWashington, DC DOH: Shannon HaderMembers of the TLC-Plus team and Advisory GroupHIV Prevention Trials NetworkMany others
Support by NIH