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 the cause 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 prevention

intervention that could have an important impact on HIV 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 pregnant mothers during labour and delivery and to new born babies (during breast feeding) significantly reduces the likelihood of MTCT.

Strategies for PrEP trials

Oral PrEP : ARVs taken regularly (daily, intermittent ?) Topical PrEP :ARV-based microbicides ARVs gels in vagina ARV vaginal rings or other products 5 (Vagina/Rectum)

Microbicides Products
Topical products to prevent HIV transmission

Could be delivered in many forms:

Gel

Gel applicator

Ring

Suppository, capsule, film

Ideally safe, effective, low cost, user friendly

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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), in 1% gel or as oral tablet
= FTC/TDF (co-formulated emtricitabine + tenofovir)
* TDF: tenofovir disoproxil fumarate: Viread * FTC: emtricitibine: Emtriva * TDF/FTC: Truvada

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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DESIGN OF PrEP TRIALS IN HUMANS

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

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DESIGN OF PrEP TRIALS IN HUMANS

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

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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
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From CL Celum, MD, MPH, at Chicago, IL: June 13, 2011, IASUSA.

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A Brief History of ART PrEP

1995 PMPA effective in macaque model 2006 HPTN-059 Phase 2 2010 iPrEX 2011 FEM-PrEP 2011 Partners PrEP 2012 MTN-003 VOICE

2005 HPTN-050 Phase 1

2007 TDF PrEP Study

2010 CAPRISA 004 Phase 2B

2011 HPTN-052

2011 TDF2

2011 FACTS-001

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Jul 2010: A landmark year for microbicides

Phase 2B trial in 889 women, ages CAPRISA 004: 18 years in Durban, South Africa Pericoital 1% tenofovir gel Coitally dependent: gel within 12 hours 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

Abdool Karim et al, Science July 2010

( mild, self-limiting diarrhea compared to placebo) Abdool Karim et al, Science, July 2010
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CAPRISA 004 assessed the safety and effectiveness 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 possible within 12 hours After sex, no more than Two doses in 24 hours asap
12 hrs 72 hrs

asap

Onset of labour

Delivery

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Abdool Karim et al, Science, July 2010

Effectiveness of tenofovir gel in preventing HIV infection

Tenofovir # HIV infections
Women-years (# women)

Placebo 60
660.7 (444)

38
680.6 (445)

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 daily oral 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 to enrollment

Completed 2010; excellent safety profile

nausea 1st month Small decrease in bone mineral density (Mulligan CROI 94LB)
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From CL Celum, MD, MPH, at Chicago, IL: June 13, 2011, IASUSA.

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Fully enrolled as of December 2009

Sites Participants
San Francisco Boston Iquitos Guayaquil Lima Sao Paulo Rio de Janeiro Cape Town
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11 2,499

Chiang Mai

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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
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President Barack Obama

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UPDATE: President Barack Obama reacted to the news Nov. 23, saying,

"I am encouraged by this announcement of groundbreaking research on HIV prevention. While more work is needed, these kinds of studies could mark the beginning of a new era in HIV prevention. 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 for efficacy

July 13th, 2011

CDC announce positive TDF2 results

July 13th, 2011
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What does the research say about PrEP?

CAPRISA 004 Study participants Heterosexual women iPrEx Men who have sex with men (MSM) and trans women Daily Truvada pill Partners PrEP Serodiscordant heterosexual couples Daily Viread pill Daily Truvada pill TDF2 Heterosexual men and women

Type of PrEP Reduced risk of HIV infection

Overall Consistent users

Coital tenofovir gel (vaginal)

Daily Truvada pill

39% 54% Diarrhea

44% 73% Nausea Headache Decrease in kidney function and bone density Drug resistance

62% (Viread) 73% (Truvada) Nausea Diarrhea

63% 78% Nausea Vomiting Dizziness

Safety concerns

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HPTN 052 : Treatment as Prevention

1763 Couples randomized to receive immediate (n=886) or deferred ART (n= 877) in 9 countries in Africa, the Americas, and Asia Median follow-up: 1.7 years
Study Arm Follow-up (PY)* Incidence/100PY [95% CI] Linked Immediate Delayed 1585 1567 Overall

0.1
[0.0 0.4]

0.3
[0.1 0.6]

1.7
[1.1 2.5]

2.2
[1.6 3.1]

*Person-years specific for transmission events

96% lower HIV incidence in early treatment group

Cohen MS, et al. IAS 27 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print] 27

HPTN 052 : Treatment as Prevention

Effectiveness of HIV Prevention

HPTN-052 Partners PrEP CDC TDF2 Circumcision iPrEX 96% 73% 63% 54% 44%

STI
CAPRISA RV144

42%
39% 31%

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Abdool Karim & Abdool Karim. Lancet 2011

Ongoing PrEP research

Study CDC 4370 (BTS) VOICE (MTN003)

Location Thailand

Population 2,400 people who use injection drugs 5,000 heterosexual women

Intervention Daily Viread pill

Completion 2012

East/South Africa

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
BTS
IDU
Serodiscordant

MSM

iPrEX
CAPRISA 004

Partner PrEP
Couples

High-risk Women

TDF2

Safety, adherence, & efficacy

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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 ?

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It is exciting Proof of concept for ARV prophylaxis Proof of concept for microbicides

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 ?)

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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 Prevention

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The need for COMPREHENSIVE HIV PREVNETION PACKAGES

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Chemoprophylaxis: Short Term HIV Vaccine: Long Term

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I m your good friend, Please wear me on !

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Behavioral research and biomedical interventions

Behavior

Biomedical prevention

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For more information

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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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Royal Flora Garden, Chiang Mai

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FEM-PrEP
1,951 women randomized to receive Truvada or 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 couples randomized to receive Viread, Truvada, or placebo Kenya and Uganda Placebo Viread HIV EP 47 18 Efficacy% CI 34-78

Truvada
IAS Jul 2011

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63 73

49-85
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CDC TDF2 Study

1,200 men and women randomized to Truvada or placebo Botswana HIV EP 24 9 Efficacy % CI 22-83

Placebo Truvada
IAS Jul 2011

63

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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
TOTAL SAMPLE (5000)

Oral Pill (3000)

Vaginal Gel (2000)

Truvada (1000)

Tenofovir (1000)

Oral Placebo (1000)

Tenofovir Gel (1000)

Placebo Gel (1000)

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Funded by NIH and BMGF

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 & resistance in heterosexual & IDU populations
Drug costs, targeting, & delivery of tenofovir-based PrEP: key to costeffectiveness & implementation Roll-out of PrEP will be complex: Demonstration projects to inform implementation Future is exciting with difficult challenges: Prioritization & efficient testing of new products, delivery modes, & integration into combination prevention Treatment is prevention: HPTN 052 confirms observational data; need to expand ART coverage

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