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STATUS AND TRENDS IN BIOMEDICAL HIV PREVENTION

Kenneth H. Mayer, MDCAPACITY BUILDING IN HIV PREVENTION IN PERU

UNAIDS, NOVEMBER 13TH, 2014

HIV Prevention: Increasing Choices

• Barrier protection• Blood screening• Harm reduction for PWUD• ART

- Maternal-to-child transmission- Decrease partner’s viral load- Treatment of acute HIV infection

● Barrier protection● Circumcision● Vaccines● Immunoprophylaxis● ART - Oral - Topical (Gel, Film, Ring) - Injectable

● Condom promotion● Individual-level interventions● Couples interventions● Community-based interventions● Structural interventions

Decrease Sourceof HIV Infection

Decrease Host Susceptibilityto HIV Infection

Alter Behavior:Exposure, Adherence

.

Evidence Supports Combination ART for Prevention of HIV Transmission

● Transmission only occurs from persons with HIV

● HIV RNA level is single greatest risk factor for HIV transmission

● Combination ART can lower HIV RNA level to undetectable levels

● Observational evidence in heterosexual couples

● Previous modeling work suggests considerable potential

● Knowing one’s HIV status is key to prevention with combination ART

● When to start combination ART is not known for certainty

HPTN 052:Stable Heterosexual Couples

Phase 3 study Americas, African, Asian sites

(n=1763 couples)

Stable, healthy, sexually active,serodiscordant couples

CD4 350-550 cells/mm3

Randomization1:1

Early ARTCD4 350 to 550 cells/mm3

Primary Endpoints• Transmission

- Virologically linked transmission events

• Clinical- WHO stage 4 clinical events

- Pulmonary TB

- Severe bacterial infection and/or death

Similar baseline demographic characteristicsand sexual history/behavior both arms

and between HIV-negative partner and HIV-positive, treatment naïve index patient

Cohen MS, et al. N Engl J Med. 2011;365:493-505.

Delayed ARTCD4 <250 cells/mm3

HPTN 052: HIV Prevention inStable Heterosexual Couples

● DSMB halts trials after a median follow-up: 1.7 years

- HIV RNA <400 copies/mL• Early ART: 90%

• Delayed ART: 93%

● Linked HIV transmission to HIV-negative partner (n=28)

- Early therapy (n=1)• 0.1 per 100 person-years

- Delayed therapy (n=27)• 1.7 per 100 person-years

● Early ART led to a 96% reduction of sexual transmission of HIV in serodiscordant couples

Cu

mu

lati

ve P

rob

abili

ty

0 1 2 3 4 5

Linked HIV Transmission

EarlyART

DelayedART

Cohen MS, et al. N Engl J Med. 2011;365:493-505.

Years

HR: 0.04(95% CI 0.01-0.27)

(P<0.001)

Ecologic Studies:Impact of ART on New HIV Diagnoses

Washington, DC San FranciscoBritish Columbia,

Canada Denmark

Data source Health departmentAIDS surveillance

Health departmentAIDS surveillance

Disease and treatment databases

National HIV surveillance data and

behavioral surveys

Estimation of suppressive ART

Annual mean and total or most recent

HIV RNA

Annual mean and total CVL

Number infected receiving ART

Prevalence positive on ART

Sexual risk behaviors

Estimation of HIV incidence

Reported new diagnoses

Report new diagnoses (STARHS method)

New positive test/100 population

Annual number of MSM notified as HIV infected

Results No association between CVL and

new diagnoses

Reductions in CVL associated with fewer

new infections (though not with STARHS

method)

Rising numbers of ART recipients and HIV RNA

<500 copies/mL associated with decreased HIV diagnoses/year

Increasing numbers treated coincides with

stable numbers of newly notified HIV positives

suggests reduced infectiousness

Castel AD, et al. AIDS. 2012;26:345-353.Das M, et al. PloS One. 2010;5:e11068.Montaner JS, et al. Lancet. 2010;376:532-539.Cowen S, et al. 18th IAC. Vienna, 2010. Abstract MoAC0103.

CVL: community viral load.

Even with optimal implementation of 2013 WHO guidance, HIV incidence remains too high

(Futures Group, 2013)

What about those who did not benefit?

• Adherence• Engaged in study, but

not interested in PrEP• Medical Mistrust• Pharmacology• Genital inflammation (STI, sexual violence?)

(Auerbach, Marrazzo, VanDamme, Van der Straten, Stadler, Tolley, Hendrix, Abdool Karim, Saethre, Corneli)

PrEP clinical questions

Symptoms: Start-up, GI, uncommon

Renal: uncommon with monitoring

Bone: focus on youth ATN 110/113

Selection for resistance: rare, almost all 184V

Risk compensation vs. reaching those at risk

Other STI: need for frequent monitoring; HSV-2?

Other approaches: Two ring studies; FACTS 001

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High Levels of Adherence are Feasible: US PrEP Demonstration Project: (2012-2014)

● STD clinics in San Francisco, Miami, Washington, DC (n=831)

- MSM, transgender women Clinic referrals (63%)

- Self-referrals (37%): and clinic referrals

● Offered up to 48 weeks of open-label emtricitabine/tenofovir DF

- Accepted PrEP: 60.4% • 77% had TDF-DP levels

consistent with taking >4 doses/week

● PrEP use associated with higher-risk sexual behaviors

0

10

20

30

40

50

60

<250 250-550 >550-950BLD

Sam

ples

(%)

18%

43%

14%

5%2%

Tenofovir-DP Levels (Week 4)

>950

Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954.; R Grant, AIDS 2014, LB Tuesday

2%

11%

27%

4% 4%

52%

43%40%

35%

Miami (n=157)Washington, DC (n=100)San Francisco (n=300)

Doses/Week: <2 <2 2 4 >4

Tenofovir-DP (fmol/punch)*BLD: below limit of detection.

0%

*femtomole/punch: measure of flux density.

How to improve chemoprophylaxis effectiveness?

Intravaginal rings

Vaginal & Rectal Microbicides Injectables:

ARVs and mAbs

Novel adherence strategies

Alternative delivery systems and formulations

New oral PrEP drugs and dosing strategies

“On Demand”

Used around time of intercourse

For those who have intermittent sex or want more direct control over their protection

Priorities for New Technologies

Sustained Release

User-initiated, does not require daily action

Should increase adherence and effectiveness

Long-acting Injectable

Co-administration of products targeting separate indications

Equal duration of effectiveness for the co-administered products

Available & Emerging Multipurpose Technologies

Drug combinations

Injectable ART, mAbs , HC

Drug/device combinations

Electrospun Nanofibers/Films

Female Condom

Male Condom

The future of MPTs…protection from HIV, other STDs, +/- pregnancy

Use rates are low in some settings, difficult to negotiate

Long Acting Injectable Nano-Suspensions:

• NNRTI (Rilpivirine)• Oral formulation in CompleraTM

• Long acting: up to 3 months?• Multiple trials:

– Dose ranging PK; PK/PD– Phase-2: HPTN 076

• Integrase inhibitor• Similar to Dolutegravir• Safe in humans with oral run-in• Activity up to 3 months?• NHP model efficacy• Phase 2: Éclair and HPTN 077

Cabotegravir (GSK ‘744; ViiV)TMC278LA (Rilpivirine; PATH)

Antibody targets to block HIV transmission Target Class Antibodies (specific targets)HIV specific antigens NIH45-46 (CD4 binding site)

3BNC117 and 3BNC60 (CD4 binding site)10-1074 (glycan/V3 loop)PGT121 (glycan/V3 loop)VRC01 (gp120)10E8 (several sites)

HIV binding sites on macrophages Ibalizumab (CD4 binding site)PRO140 (CCR5)

Host derived antigens on both free virus and infected cells

Anti-CD36Anti-LFA-1/CD11aAnti-TSG101Anti-GM3

Uninfected Dendritic and epithelial cells

Anti-CD169Anti-ICAM-1

Reproductive tract coating antigens HC4 (SAGA-1, male tract specific glycoform of CD52)

Ongoing and Planned Phase 3/4 Research, Including Demonstration Projects

¨ Phase 3 studies are continuing to evaluate PrEP in various demographic groups

¨ Gilead is committed to post-marketing demonstration studies in the U.S. and globally

¨ Collaborators: ANRS, CDC, FHI, MRC, NIAID (DAIDS), NICHD (ATN), SFDPH, U. Washington, and Gilead Sciences

Population Studies Participants

MSM 17 14,100

Heterosexual Men & WomenSerodiscordant Couples 8 10,201

Total 25 24,301

ANRS = French National Agency for AIDS Research; CDC = Centers for Disease Control and Prevention; FHI = Family Health International; MRC = Medical Research Council (UK); NIAID = National Institute of Allergy and Infectious Diseases; DAIDS = Division of AIDS; NICHD = National Institute of Child Health and Human Development; SFDPH = San Francisco Department of Public Health

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Lively Discussion and Debate in the Blogosphere

• Brief video testimonials developed regarding PrEP users’ decisions and motivations to take PrEP and experiences taking PrEP

• Also: www.myprepexperience.blogspot.com AIDS Foundation of Chicago

P<0.001

P=0.08

Proportion of Participants Reporting PrEP Awareness, Interest, and Use (Mayer, HIV R4P, 2014)

P=0.002

P<0.001

P=0.002

P=0.004

Overall Sample 6683/4759

Reported Condomless Anal Sex 3826/3141

Factors Associated with PrEP Use among US MSM Multivariable Model, Manhunt Survey, CROI, 2014

New technologies and PrEP adherence

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↑ treatment adherence with text messaging (Lester, Lancet, 2010)

Wisepill: cell-phone size device, provides real time signal when pillbox opened

Life-Steps intervention has been modified for PrEP use, including daily SMS with pts (Safren)

Next step counseling in iPrEX Ole, augmented by electronic diary in SF and Chicago was associated with ↑ adherence (Amico/Hosek)

Feedback on drug levels been studied as adjunct to counseling (Landovitz)

SexPro App being developed (Buchbinder/Lama) Augmented lower tech approaches,

e.g. home visits are effective (Haberer, JAIDS, 2014)

Purview paradox: contradictory beliefs about which providers will prescribe PrEP

(Krakower, AIDS and Behavior, 2014)

HIV providers:Primary care providers are in the best position

to prescribe PrEPPrimary care providers: It would not be feasible

to prescribe PrEP

www.thefenwayinstitute.org/prepinfo

Cost effectiveness of PrEP improves when offered to highest risk persons

Buchbinder, Lancet ID, 2014

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Policy -HIV testing guidelines -HIV treatment guidelines -Siloed funding sources

-Treatment funding - Prevention

-Coordination

-Quality indicators -Service

coordin. -Reim- bursement

-Workforce - Incarceration

Eco-Social Issues and New Prevention Technologies

Community -Stigma -Poverty -Social norms -Neighborhood -Employment -Corrections

Health System -Organization -CBOs -Clinic proximity -Clinic culture -Appointments -Supportive svcs -Integrated svcs

-Sex Partners -Family -Friends -Social Networks -Med Providers -Case Managers Communication Factors -Trust -Communication -Longevity -Concordance

Relations

Individual

Predisposing

-Age-Race/ethnicity-Sex- Gender-Sexuality-Mental health-Substance use

Enabling

-Insurance-Housing-Transport-Income-Social support-Food security-Correctional system

Need

-Symptoms-Concomitant illness-Health beliefs-Past experiences

Decrease inHIV Transmission

Maintain ViralSuppression

Treat

Enroll in Care

Address concomitant concerns:depression, substance use, relationship

dynamics

Combination Antiretroviral Prevention

HIV Negative

Test

Interventions to Increase Testing

PositivePrevention

LinkageTo Care

Adherence to ART

ART Initiation

.

Risk Assessment PrEP, Adherence

Counseling

HIV Positive

Many thanksSalim Abdool KarimRick AlticeRivet AmicoSusan BuchbinderNomita ChandhiokHeidi CraneWafaa El-SadrDavid GliddenRobert GrantTrip GulickBethany HoltDoug KrakowerRaphy LandovitzAlbert LiuAlex RinehartJim RooneyZeda RosenbergSteve SafrenRochell WalenskyMitchell WarrenKevin Whaley

The Fenway Institute colleaguesNIAID, NIMH, NICHD, CDC, HRSA, Mass DPH, Gilead, ViiV, Merck HPTN, HVTN, MTN, ATNwww.thefenwayinstitute.org