Antiretroviral Therapy: An HIV Prevention Strategy? Wafaa El-Sadr, MD, MPH Columbia University Harlem Hospital New York.

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