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

Persons Living with HIV/AIDS million ( million) worldwide Latin America 1.6 million E. Europe/Central Asia 1.6 million E. Asia/Pacific 800,000 Sub-Saharan Africa 22.5 million N. Africa/Mid-East 380,000 South/S.E. Asia 4.0 million Caribbean230,000 Source: UNAIDS, AIDS Epidemic Update, December 2009 North America 1.3 million Oceana75,000 Western & Central Europe760,000

Use of ART for PMTCT

HIV RNA Levels Associated with HIV Transmission Risk Viral load (HIV-1 RNA copies/ml) and HIV transmission Transmission rate per 100 Person-Years < > Quinn TC, et al. NEJM 2000; Fideli U, et al. AIDS Res Hum Retrovir 2001 < > < > All subjects Male-to-Female Transmission Female-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/mm 3 on 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, 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):

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: DeGruttola V, et al. Controlling the HIV epidemic, without a vaccine! AIDS 2008; 22: 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, 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 safer behaviors 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 Initiation of 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 ART Mohammed, CROI % 39%

Percentage HIV Tested Country % Tested in preceding 12 months Woman Men Congo Cote dIvoire Ethiopia2.3 Namibia Rwanda Swaziland Uganda Zambia Zimbabwe7.0 United States 10%

% 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, (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% – CD : 8.2% – CD : 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 ) NYC DOHMH surveillance 2007 Hanna et al 2008

Positive Prevention

Positive Prevention Interventions Intervention Name Healthy Relationship CLEARWILLOWSUMIT Enhanced Peer-Led Options Study Size SettingCommunity AIDS Service Organization Community agency, residence or community site Study site and HIV service clinic Study siteHIV care clinic Unit of Delivery GroupIndividualGroup Individual DelivererMale 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 UseUVI; condom use; STI UAR with non HIV+ partner UAI, UVI, UAR, UVR, UIO

Linkage to Care

25 Time from HIV Diagnosis to Care Entry* 1,3401,8271,6351,5021,3421,510 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 ) – Diagnosis in corrections, STI or TB clinic (HR:1.3, 95% CI; ) – Non-white race/ethnicity (HR: 1.8; 95% CI ) – Injection drug use (HR: 1.3; 95% CI ) – Foreign born (HR: 1.1; 95% CI ) Torian et al 2008

Treatment with ART

When to Start Antiretroviral Therapy LaterEarlier

Early versus Later ART Possible BenefitsPossible 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/mm 3 Early ART Group Initiate ART immediately following randomization N=2,000 for definitive trial Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,000 for definitive trial Serious AIDS, Non-AIDS Events or Death

HPTN 052 HIV-infected subjects with CD4 350 to 550cells/µL with discordant partner Immediate ART cells/uL Deferred ART CD4 200 AZT+3TC+EFV Endpoints: i) HIV Transmission to partners ii) OIs and clinical Events ii) OIs and clinical Events iii) ART toxicity iii) ART toxicity Randomization Thailand, South Africa, Botswana, 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, 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. Testing II. Linkage to care III. Viral suppression IV. Positive prevention V. 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 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 % prevalence Population Prevalence REF: Shannon Hader. CROI 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%

41 HIV Rapid Testing Expansion in DC 68.4% increase in number of tests done in 1 yr N=43,271N=72,864 97% of new HIV positives were identified in clinical settings 94% of new HIV positives were identified in clinical settings

Study Components I. 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

Study Components II. 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 < Volpp, Troxel, Pauly et al, New England Journal of Medicine. 2009; 360(7):

Study Components IV. 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 Components Prevention 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 Components V. 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 Hall NYC DOHMH: Blayne Cutler and Lucia Torian Washington, DC DOH: Shannon Hader Members of the TLC-Plus team and Advisory Group HIV Prevention Trials Network Many others Support by NIH