Microbicides and PrEP (Suwat Chariyalertsak)

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Microbicides and PrEP

Suwat Chariyalertsak MD., Dr.PH

Research Institute for Health Sciences,

Chiang Mai University

Journalists – 2 – Journalist Program, BKK, Thailand

11 Sep 2011

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PRE-EXPOSURE PROPHYLAXSIS

(PrEP)

PrEP use for people who are vulnerable to get DISEASE

PrEP is the long term exposure to a prophylactic

treatment (drugs) of a disease prior to exposure to thecause of that disease.(eg; virus, bacteria, protozoa, etc)

The prophylactic treatment (drugs) will already be in

place when exposure occurs, and may either be able to

prevent infection or treat it.

PrEP (ARV drugs) is a potential new HIV preventionintervention that could have an important impact onHIV prevention globally in the FUTURE !!.

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Proof of concept

Malaria: Travellers to regions where malaria

is endemic are familiar with the concept of taking Larium prior to departure, while in the

country and post-return home.

PMTCT: Providing ARVs to pregnantmothers during labour and delivery and to

new born babies (during breast feeding)

significantly reduces the likelihood of MTCT. 4



Strategies for PrEP trials

Oral PrEP :-ARVs taken regularly

(daily, intermittent ?)

Topical PrEP :-

ARV-basedmicrobicides

ARVs gels in vagina

ARV vaginal rings or

other products(Vagina/Rectum)

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Microbicides Products

• Topical products to prevent HIV transmission

• Could be delivered in many forms:

• Ideally safe, effective, low cost, user friendly

Gel applicator Ring Suppository, capsule, filmGel

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= FTC/TDF (co-formulated emtricitabine + tenofovir)

= TDF (tenofovir), in 1% gel or as oral tablet

TDF and FTC/TDF for PrEP

Among the anti-HIV medications currently

available, two most used in animal and human

trials of PrEP:

* TDF: tenofovir disoproxil fumarate:Viread ®

* FTC: emtricitibine: Emtriva ®

* TDF/FTC: Truvada ® 8



How do tenofovir (TDF) and emtricitabine-tenofovir

(FTC/TDF) measure up?

Potent:

• Broad antiviral activity (all HIV-1 subtypes, HIV-1 &-2, R5 & X4 viruses)

• Long half-life compare with other ARV drugs

• Could block initial infection (act early in HIV life cycle)

• FTC is rapidly active (TDF takes longer to be metabolized)

Safe: Favorable safety and tolerability

Easy: Low pill burden, no food restrictions, few drug interactions

However, TDF & FTC/TDF in first line treatment regimens: Concerns about resistance (K65R, M184V) & NRTI cross-resistance

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Placebo controlled, double-blind, randomized (2-4 arms)

Primary endpoint is efficacy (Prevent HIV infection !)

Go with comprehensive HIV prevention packages ;condoms, risk reduction counseling & STI treatment

Safety endpoints (ARV drugs toxicity !)

Phosphorus (bone mineralization) & fractures

Kidney (renal insufficiency)

Hepatitis flares in persons with chronic Hepatitis B

DESIGN OF PrEP TRIALS IN HUMANS

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Drug Adherence (How to measure !)

Changing risk behavior over time

In seroconverters (Be HIV infected)

Resistance to TDF or FTC/TDF

Effect on HIV disease progression

DESIGN OF PrEP TRIALS IN HUMANS

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The life & times of PrEP ; 1st decade

2001 – PrEP first proposed

2003 – Cambodia PrEP trial proposed with sex workers

2004 – Protests at Bangkok AIDS conference (Study in IDU)

2005 – West Africa phase II trial of tenofovir in sex workers

• Cameroon site stopped due to community concerns

2006 – Safety of tenofovir reported at Toronto AIDS conference

2007-9 – Phase IIB & III trials start in IDUs, MSM & heterosexuals

• Bangkok IDU, CAPRISA 004, iPrEx, Botswana, Partners

PrEP, VOICE, & FemPrEP trials

From CL Celum, MD, MPH, at Chicago, IL: June 13, 2011, IAS –USA.

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A Brief History of ART PrEP

1995PMPA effective

in macaquemodel

2005HPTN-050

Phase 1

2006HPTN-059Phase 2

2010CAPRISA 004

Phase 2B

2010iPrEX

2011FEM-PrEP

2011HPTN-052

2011Partners

PrEP

2011TDF2

2011Partners

PrEP

2012MTN-003VOICE

2007TDFPrEPStudy

2011FACTS-001

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Jul 2010: A landmark year for microbicides

Phase 2B trial in 889 women, ages≥18 years in Durban, South Africa

Coitally dependent: gel within 12hours before & 12 hours after sex,

max. 2 applications in 24 hours

Study population: Young women(mean age 23), unmarried, from rural(69%) & urban (31%) settings

Completed 2010: Good safety profile (↑ mild, self -limiting diarrhea compared toplacebo)

CAPRISA 004:

Pericoital 1% tenofovir gel

Abdool Karim et al, Science July 2010

Abdool Karim et al, Science, July 201015



CAPRISA 004 assessed the safety andeffectiveness of 1% tenofovir gel

BAT 24 coitally-related gel use◦ Insert 1 gel up to 12 hours Before

sex,

◦

insert 1 gel as soon as possiblewithin 12 hours After sex,

◦ no more than Two doses in 24 hours

asapasap72hrs

12hrs

Onset oflabour

Delivery

Abdool Karim et al, Science, July 2010

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Effectiveness of tenofovir gel inpreventing HIV infection

Tenofovir Placebo

# HIV infections 38 60

Women-years (# women) 680.6 (445) 660.7 (444)

HIV incidence

(per 100 women-years)5.6 9.1

Incidence rate ratio: 0.61 (CI: 0.4 to 0.94); p = 0.017

39% lower HIV incidence in tenofovir gel group

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Nov 2010: A landmark year for oral PrEP for

HIV-1 prevention with iPrEx

2499 MSM, randomized 1:1 dailyoral FTC/TDF vs placebo

11 sites (Brazil, Ecuador, Peru,South Africa, Thailand, US)

Young high-risk MSM:• 50% <25 yrs

• Median 18 partners in 12 wks prior toenrollment

Completed 2010; excellent safetyprofile• ↑ nausea 1st month

• Small decrease in bone mineraldensity (Mulligan CROI 94LB)

From CL Celum, MD, MPH, at Chicago, IL: June 13, 2011, IAS –USA.

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Fully enrolled as of December 2009

Lima

IquitosGuayaquil

Sao Paulo

Rio de Janeiro

Boston

San Francisco

Cape Town

Chiang Mai

Sites 11

Participants 2,499

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iPrEx: Adherence is critical to efficacy

Efficacy by as-treated analysis(data as of Nov 21, 2010)

High (≥ 90% adherence; 49% of visits)

68% efficacy

Intermediate (50-90% adherence; 33% of visits)

34% efficacy

Low (< 50% adherence;18% of visits)16% efficacy

• 9% of seroconverters had

detectable drug at first HIV+ visit

- vs 51% of nonseroconverters

Grant et al, NEJM 2010 22



President Barack Obama UPDATE: President Barack Obama

reacted to the news Nov. 23, saying,

"I am encouraged by this announcementof groundbreaking research on HIV prevention . While more work is needed,these kinds of studies could mark the

beginning of a new era in HIVprevention. As this research continues,the importance of using proven HIV

prevention methods cannot be

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Recent Events in 2011: Exciting

FEM-PrEP study stopped for futility April 18th, 2011 (Show no efficacy ?)

HPTN-052 delayed treatment arm

stopped for efficacy (Rx as Prevention) May 12th, 2011

Partners PrEP placebo arm stopped forefficacy July 13th, 2011

CDC announce positive TDF2 results July 13th, 2011

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What does the research say about PrEP?

CAPRISA 004 iPrEx Partners PrEP TDF2

Study participants Heterosexualwomen Men who havesex with men(MSM) and transwomen

Serodiscordantheterosexualcouples

Heterosexual menand women

Type of PrEP Coital tenofovirgel (vaginal)

Daily Truvada pill Daily Viread pill

Daily Truvada pill

Daily Truvada pill

Reduced risk of HIV infection

Overall 39% 44% 62% (Viread)

73% (Truvada)

63%

Consistent users 54% 73% - 78%

Safety concerns • Diarrhea • Nausea• Headache

• Decrease inkidney functionand bone density

• Drug resistance

• Nausea• Diarrhea

• Nausea• Vomiting

• Dizziness

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HPTN 052 : Treatment as Prevention

• 1763 Couples randomized to receive immediate (n=886) or deferredART (n= 877) in 9 countries in Africa, the Americas, and Asia

• Median follow-up: 1.7 years

96% lower HIV incidence in early treatment group

Study Arm Follow-up (PY)*

Incidence/100PY[95% CI]

Linked Overall

Immediate 15850.1

[0.0 – 0.4]

0.3[0.1 – 0.6]

Delayed 15671.7

[1.1 – 2.5]

2.2[1.6 – 3.1]

*Person-years specific for transmission events

Cohen MS, et al. IAS 2011. Abstract MOAX0102.Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]

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HPTN 052 : Treatment as Prevention



Effectiveness of HIV Prevention

HPTN-052

Partners PrEP

CDC TDF2

Circumcision

iPrEX

STI

CAPRISA

RV144

96%

73%

63%

54%

44%

42%

39%

31%

Abdool Karim & Abdool Karim. Lancet 201129



Ongoing PrEP research

Study Location Population Intervention Completion

CDC 4370

(BTS)

Thailand 2,400 people whouse injectiondrugs

• Daily Viread pill 2012

VOICE

(MTN003)

East/South

Africa

5,000 heterosexual

women

• Daily Viread pill

• Daily Truvada pill• Daily tenofovir gel

2013

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Ongoing PrEP trials will complete different

parts of the ‘PrEP Puzzle’

Safety, adherence, & efficacy

IDU

MSM

Serodiscordant

Couples

High-risk

Women

iPrEX

Partner PrEPCAPRISA 004

TDF2

BTS

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G l f i l & l ARV f HIV



Goals of topical & oral ARVs for HIV

prevention

• Right drug(safe, effective, minimal resistance)

• Right place(sufficient concentrations at site of exposure)

•Right time

(short onset of activity & long half-life

to optimize efficacy with variable adherence)

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What is next for ARV-PrEP ?

It is exciting

Proof of concept for ARV

prophylaxisProof of concept formicrobicides

Is it sufficient

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What concerns does the use of PrEP raise?

• Side-effects and toxicity

• Drug resistance

• Adherence

• Risk compensation

• Access of ARV drugs

•Cost (Who will pay ?)36

K I l t ti Q ti



Key Implementation Questions

for TDF gel & oral FTC/TDF

• Whom to target?

– Who is high risk? How to ascertain?

– HIV discordant couples?

–

Heterosexual populations – no data currently

• Where to deliver?

– STD clinics? HIV clinics?

–

Public health facilities? Primary care clinics? Pharmacies?

• For public health (i.e., not “boutique”) impact = high

access and coverage of highest risk persons is required

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No single bullet for HIV



No single bullet for HIVPrevention The need for

COMPREHENSIVE HIV

PREVNETION PACKAGES

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Ch h l i Sh t T



Chemoprophylaxis: Short Term

HIV Vaccine: Long Term

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I’ m your good

friend, Pleasewear me on !

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Behavioral research and biomedicalinterventions

Biomedicalprevention

Behavior

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For more information…

PrEP:www.prepwatch.org

Microbicides

www.global-campaign.org

www.rectalmicrobicides.org

www.ipm-microbicides.org

www.microbicide.org (Alliance for Microbicide Development)

Treatment of HIV+ partner www.hptn.org (look under HPTN052)

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http://www.prepwatch.org/

http://www.global-campaign.org/

http://www.rectalmicrobicides.org/

http://www.ipm-microbicides.org/

http://www.microbicide.org/

http://www.hptn.org/

http://www.hptn.org/

http://www.microbicide.org/




http://www.rectalmicrobicides.org/




http://www.prepwatch.org/



Royal Flora Garden, Chiang Mai



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FEM-PrEP

1,951 women randomized to receive Truvadaor placebo

Kenya, South Africa, and Tanzania

Study stopped because of futility 56 HIV endpoints

Truvada: N = 28

Placebo: N = 28

Possible explanations for lack of efficacy Poor adherence or drug sharing

Differential compartmental Pharmaco-kinetic (PK)

Chance

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Partners PrEP Study

4,758 HIV serodiscordant couplesrandomized to receive Viread, Truvada, orplacebo

Kenya and Uganda

HIV EP Efficacy% CI

Placebo 47

Viread 18 63 34-78

Truvada 13 73 49-85

IAS Jul 2011 48



CDC TDF2 Study

1,200 men and women randomized toTruvada or placebo

Botswana

HIV EP Efficacy % CI

Placebo 24

Truvada 9 63 22-83

IAS Jul 201149

CDC 4370



CDC 4370

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VOICE: Vaginal & Oral Interventions

to Control the Epidemic

Objectives: Estimate the effectiveness of daily tenofovir 1% gel, oral

TDF, and oral FTC/TDF in preventing HIV in women

Evaluate the extended safety of daily tenofovir 1% gel,

oral TDF, and oral FTC/TDF in preventing HIV in women Evaluate adherence and acceptability to the daily

vaginal and oral regiments

Assess the selection of HIV-1 drug resistance in women

acquiring HIV-1 in the study

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• Five study groups & 2 sequential randomizations.

• Women will use product for average of 21 months

TOTALSAMPLE

(5000)

Oral Pill

(3000)

Vaginal Gel

(2000)

Truvada(1000)

Tenofovir(1000)

Oral Placebo(1000)

Tenofovir Gel(1000)

Placebo Gel(1000)

Funded by NIH and BMGF

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Summary ARVs for prevention in 2011



Summary: ARVs for prevention in 2011

• Initial proof of concept of topical & oral tenofovir-based PrEP: CAPRISA

004 , iPrEx, Partner PrEP, TDF2

• Importance of ongoing PrEP trials: Safety, efficacy, adherence & resistancein heterosexual & IDU populations

• Drug costs, targeting, & delivery of tenofovir-based PrEP: key to cost-effectiveness & implementation

• Roll-out of PrEP will be complex: Demonstration projects to informimplementation

•

Future is exciting with difficult challenges: Prioritization & efficient testingof new products, delivery modes, & integration into combinationprevention

• Treatment is prevention: HPTN 052 confirms observational data; need toexpand ART coverage

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Microbicides and PrEP (Suwat Chariyalertsak)

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