www.aids2014.org

Stepping up the pace: New Prevention Technologies

Kenneth H. Mayer Fenway Health Beth Israel Deaconess Medical Center Harvard Medical School Harvard School of Public Health

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

.

www.aids2014.org

New Prevention Technologies • Isn’t treatment expansion sufficient?• PrEP: If used consistently, will work• How to optimize delivery? • New Pills, Rings, Films, Injectables• Multi-Purpose Technologies• Immunoprophylactics• E-Technology and HIV prevention• Next Gen Circumcision• Combination Prevention for PWUD• The cost of success vs. status quo• Choice: One size will never fit all

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)

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

“On demand” Products: Gels Tenofovir Gel (CONRAD)

Effective in preventing HIV (39%) and HSV-2 (51%) in CAPRISA 004, but not VOICE

Confirmatory trial (FACTS 001) :2,900 HIV-negative 18-30 yr old South African women enrolled, evaluating coitally-dependent gel, results 2015

Rectal optimized gel being studied in Phase 2 study in 360 MSM and transgender women in MTN017 in Peru, South Africa, Thailand and US

New Topical Gels MIV-150 (NNRTI) + Zinc Acetate + LNG (Pop Council) Griffithsin: inhibits gp120 and gp41 binding

(NCI/Palmer) 5P12-RANTES: co-receptor blocker (Mintaka) IQP-0528: NNRTI and entry blocker (IMquest)

Maraviroc• CCR5 blocker with established safety profile as marketed

oral therapeutic (Pfizer/ViiV)• Phase II study for oral PrEP +/-FTC or TDF (HPTN 069) 400 MSM/200 women

• Licensed to IPM in 2008 for microbicide indication in developing world

• Clinical development:o Maraviroc rings alone and

in combination with dapivirine

• Next-Gen:o Maraviroc gel (rectal use)- Magee Women’s Research Instituteo Maraviroc/tenofovir gel combination in early preclinical

development

Microbicide Rings• Long-acting: monthly or longer

o Could potentially improve adherenceo Better adherence → ↑ effectiveness

• Easy to use, comfortableo Flexible ring, can be self-insertedo Rarely felt by women or male partnerso Little or no impact on sexual activity

• Suitable for developing worldo Relatively low manufacturing costo Good safety and acceptability data

• Potential for drug combinations

Dapivirine (TMS 120)

• Highly potent ARV: NNRTI• Developed by Janssen • Originally tested as oral therapeutic • Licensed to IPM in 2004

– Development as vaginal microbicide for HIV prevention

• 15 Phase I/II safety studies (Dapivirine ring or gel)– Good safety profile in all studies to date– Safety data on more than 700 study participants

• Dapivirine Ring Licensure Program started in 2012, results expected in 2015/2016

Dapivirine Ring Licensure Program

• Long-term safety and efficacy study• 1950 participants, ongoing (2012-2015/16) in Africa

IPM 027The Ring Study

• Safety and efficacy study• 2,629 participants, ongoing (2012-2015) in Africa

MTN-020ASPIRE

• Drug-drug interactions (data analysis)• Male condom functionality (data analysis)• Female condom functionality (ongoing)• Extended use PK (ongoing)• Safety in women >45 (ongoing)• Safety in adolescents (ATN 023)

Additional safety studies

Sustained-Release Devices:Combination Intravaginal Rings (IVRs)

60-day Dapivirine + LNG IVR (IPM)

Combines the ARV dapivirine (DPV) + LNG (silicon ring) DPV+LNG ring formulation and testing are underway

90-day Tenofovir + LNG IVR (CONRAD; IPM)

Combines TFV with the hormonal contraceptive, LNG Segment or matrix formulation

30-day MZL Combination IVR (Population Council)

Combines MIV-150 + Zinc Acetate + LNG Early pharmacology studies underway

Nuvaring (Merck)

44 million users since 2002 Matrix, non-latex, novel polymer Vicriviroc and MK-2048 (ISTI) combinations under study

2. Plus Tenofovir Gel (CONRAD) SILCS barrier as a delivery device for TFV gel

Would provide a non-hormonal method of protection from pregnancy, HIV and HSV-2

Designed for effective protection for up to 24 hrs

+

1. SILCS Contraceptive Barrier (PATH, CONRAD, NICHD)

“One size fits most” silicone diaphragm that does not need to be fitted by a clinician; intended for OTC provision

6-mo typical use pregnancy rate comparable to standard fitted diaphragm when used with a contraceptive gel (10.4%)

5-yr shelf life; re-use for up to 3 yrs

“On demand” Products: Devices + Active Agents

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)

W Spreen, CROI, 2014

MPT Long Acting Injectables

+/-

2 or more drugs administered simultaneously

Long-acting Injectable

ARVs Rilpivirine

Cabotegravir

Depo ProveraCyclofem

Other HC or non-HCor STD rx?

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)

VRC01• Isolated from long term non-progressor• Binds to HIV-1 gp120 envelope protein• Prevented SHIV infection in NHP

– Protected vs. rectal, vaginal and oral challenges

• Broad and potent neutralizing activity– May provide inform development of effective vaccine

• Phase I evaluation began September, 2013 in VRC• HVTN 104 evaluating subQ and IV dosing: q monthly?• PEP for infants (IMPAACT)

• PEP for Adults?• Mucosal administration as a topical film (Anderson IPCP)

E-technology• Where people meet partners• Where people get information• Aps may enhance -self-assessment of risk -monitoring PrEP adherence

New technologies and PrEP adherence

24

↑ 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)

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

Use of taggents and pills containing electronic sensing devices under study (Van der Straten)

Augmented lower tech approaches, e.g. home visits are effective (Haberer, JAIDS, 2014)

2000-2006 2007

WHO and UNAIDS Recommendations

Medical male circumcision research to policy and scale-up – 25 years

1989 - 1999

0

5

10

15

20

25

0 20 40 60 80 100Circumcision prevalence (%)

HIV

Pre

vale

nce

(%)

Bongaarts, AIDS 1989

2008-2013

Uganda

South Africa

Kenya

2008 2009 2010 2011 2012 2013Year

5.82 million

27

Evidence-Based Strategies to Reduce HIV Transmission Among PWUD

Access to clean

needles and syringes

Opiate substitution therapyXR-NaltrexoneBuprenorphine

VoluntaryCounselingand Testing

ConsiderPrEPVoluntary

Primary & Secondary Secondary Only

Access to ART

Altice FL et al, JAIDS, 2011

Integrating Buprenorphine Into HIV Clinical Care Settings

Prescribed ART Viral Suppression

Cost effectiveness of PrEP improves when offered to highest risk persons

Buchbinder, Lancet ID, 2014

Cost effectiveness of New Prevention Technologies (R. Walensky)

Annual

HIV incidence (

%)

11                  

                 

10                                   

9                                   

8                                   

7                                   

6                                   

5                                   

4                                   

3                                   

2                                   

1

                 

                 

10 20 30 40 50 60 70 80 90PrEP efficacy (%)

CAPRISA 004

iPrEx

South Africa

cost-saving

Annual

HIV incidence (

%)

11                 

                 

10                                   

9                                   

8                                   

7                                   

6                                   

5                                   

4                                   

3                                   

2                                   

1

                 

                 

10 20 30 40 50 60 70 80 90PrEP efficacy (%)

  cost-saving  very cost-effective for South Africa (<$5,400/LY)  cost-effective for South Africa (>$5,400/LY)

cost-saving

Halve PrEP drug cost Halve PrEP drug & program costs

South Africa

iPrEx

CAPRISA 004

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

New Technologies may provide tools for more efficient risk screening

Electronic Patient Reported Outcomes, CNICS H. Crane

D. Smith JAIDS 2012

33

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

RelationsIndividual

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

Constrained Resources in an Promising Erawww.hivresourcetracking.org

www.aids2014.org

New Prevention Technologies, 2014

•PrEP works when used•New meds and dosing regimens for oral PrEP may improve uptake, ↓cost•FACTS 001 success may → 1st approved topical•Rectal gels may offer new anal protection•Rings may offer MPT opportunities•Injectable PrEP could improve adherence•↑ uptake of circumcision is important•State-of-the-art harm reduction for IDU is needed•Optimizing social media may facilitate safer sex counseling and med adherence•Vaccine and Cure research is still needed

www.aids2014.org

To Optimize New Prevention Opportunities

• Increased investment is needed Short term ↑ expense = long term cost ↓

• Increased political will is needed• Commitment to equity is needed• Respect for human rights is essential

Coercion to use new modalities is unacceptable Community input throughout development is essential

www.aids2014.org

Many thanksSalim Abdool KarimRick AlticeRivet AmicoDeborah AndersonJudith AuerbachRachel BaggaleyStef BaralSusan BuchbinderConnie CelumNomita ChandhiokHeidi CraneGustavo DoncelWafaa El-SadrDavid GliddenRobert GrantTrip GulickTim HallettGottfried HirnschallBethany HoltDoug KrakowerRaphy LandovitzSandy LehrmanAlbert LiuGita RamjeeRenee RidzonAlex RinehartJoe RomanoJim RooneyZeda RosenbergSteve SafrenJulia SamuelsonWilliam SpreenJohn StoverJim TurpinRochell WalenskyMitchell WarrenAriane Van Der StratenFulvia VeroneseKevin Whaley

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