maurice cook ( em designs group, inc.) a pill a day to keep hiv away robert m grant, april 28, 2011

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A Pill a Day To Keep HIV Away

Robert M Grant,

April 28, 2011

The HIV Pandemic

2.6 Million

New HIV Infections in 2009

41% in Young People (ages 15-24)

3

The HIV Pandemic

1.2 Million

Started Therapy in 2009

2 New Infections For Everyone Starting Therapy

MSM Have19.3 Higher Oddsof HIV Infection

Baral S, Plos Med 2007

HIV Prevention Methods With Efficacy Demonstrated by

Randomized Clinical Trialsto Lower HIV Incidence in MSM

None

• MSM and Trans Women• Randomized 1:1 Daily Oral PREP• FTC/TDF vs Placebo• Followed on Drug for:

- HIV seroconversion- Adverse Events (especially renal &

liver)- Metabolic Effects (Bone, Fat, Lipids)- HBV Flares among HBsAg+- Risk Behavior & STIs- Adherence- If infected

‣Drug Resistance‣Viral load‣Immune responses & CD4 Count

The iPrEx Study

8

Used PEP AfterHigh-Risk Sex

No PEP AfterHigh-Risk Sex

No PEPNo High-Risk

N 68 86 46HIV Infections 1 10 0Incidence 1.5% 11.6% 0%

• 200 MSM given a AZT/3TC PEP starter pack• Followed for 24 months• Main reasons for not starting PEP

– Sex with primary partner, friends advised against, concerned about side effect, thought exposure was low risk

Fully enrolled as of December 2009

Lima

IquitosGuayaquil

Sao Paulo

Rio de Janeiro

Boston

San Francisco

Cape Town

Chiang Mai

Sites 11

Participants 2499

New England Journal of Medicine, online Nov 23, 2010

FTC/TDF Placebo Total Difference Significance

Before PrEP 2 8 10 -6 P=0.06

During PrEP 48 83 131 -35 P=0.002

After PrEP 4 2 6 +2 P=0.NS

Total 54 93 147 -39 P=0.001

HIV InfectionsBefore, During, and After PREP

Grant et al, CROI 2011

Efficacy (MITT) 44% (15-63%) Through May 1, 2010Durable Through 144 Weeks in the Final Analysis

P = 0.002



Drug Levels

• Cases matched to controls by site and time on study

• Drug Detection Correlated with Seronegative Status (OR 12.9, P<0.001)• 92% reduction in

HIV risk• 95% if controlled for

Unprotected Receptive Anal Intercourse

17

Anderson et al, CROI 2010

HIV Infections During PrEP Trials

In The USAOn PrEP Off PrEP

• CDC Safety Study (US sites) 0 6 Daily Oral TDF vs Placebo 3 in placebo arm, 3 in deferred arm.

• NIH iPrEx (US Sites) 0 3 Daily Oral FTC/TDF vs. Placebo 2 in placebo arm 1 in active arm 9 weeks after stopped drug

Grohskopf, IAS Vienna 2010; Grant NEJM 2010

Nausea on History


Weight Gain


Genotypic Resistance

HIV Status at Enrollment

Infected Uninfected

PlaceboN=8

FTC/TDFN=2

PlaceboN=83

FTC/TDFN=48

65R 0 (0%) 0 (0%) 0 (0%) 0 (0%)

70E 0 (0%) 0 (0%) 0 (0%) 0 (0%)

184I 0 (0%) 1 (50%) 0 (0%) 0 (0%)

184V 1 (13%) 1 (50%) 0 (0%) 0 (0%)

TDF Resistance 0 (0%) 0 (0%) 0 (0%) 0 (0%)

FTC Resistance 1 (13%) 2 (100%) 0 (0%) 0 (0%)

Drug Resistance


HIV Resistance - Results• New HIV infections (91 samples tested)

No drug resistance in participants on Truvada 2 with minor variant drug resistance on placebo

(1 to tenofovir, 1 to emtricitabine)

• HIV infections already present at enrollment 2 cases of emtricitabine resistance Resistance dropped to undetectable levels within 6

months after stopping PrEP

HIV Cases Averted:FTC Resistance Ratio

•35 HIV Infections Averted

•2 Cases of FTC Resistance

•Ratio of 17.5

Sexual Partners


Condom Use with High Risk Sex


Will pill taking increase if people are given FTC/TDF (without placebo) and know it can be effective?

What will happen to sex practices?

Safety and acceptability of every 12 week visits

Collect more safety data over longer periods of time

Open Label Extension Aims:

• Stop Giving a Placebo

• Provide New Information • About Efficacy• About Safety

• Reassurance at week 4

• Decide to Use PrEP• Neutralize Visit Incentives

• “Next Step” Counseling• Client centered, motivational • Neutral Assessment• Focus on barriers and facilitators

• Monitor and Discuss Drug Levels

Strategiesfor Improving

PrEP Use

36

Effectiveness of tenofovir gel in preventing HIV infection in

women

36

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

By February 18, 2011, 3752 screened to enroll 1951739 Bondo, Kenya; 432 Bloemfontein, South Africa; 16 in Arusha, Tanzania.21% HIV infected at screening

90% retention, reported adherence 95%5% annual HIV incidence

56 infections: 28 placebo arm, 28 FTC/TDF armHormonal contraception used by most

66% injectable, 30% oral contraceptionPregnancy rates was 9%, mostly in the oral armPregnancy rate was higher in the FTC/TDF arm

Some mild side effects in the FTC/TDF arm

FEM-PrEP Facts

Possible ExplanationsLikely 2 or more of the following

Bad luck (chance)Low adherencePoor drug penetration in vaginal

tissuesSex hormone FTC interactions

Not likely, but possibleUnblinding by side effectsDrug sharing

Drug Testing and Resistance Testing Will Tell

TFV & TFV-DP by Route & SiteMTN-001: Hendrix et al CROI 2011

8

7

6

5

4

3

2

1

0

-1

-2

Route

Dual

Oral

Vaginal

• Vaginal dosing achieves active drug (TFV-DP) concentrations in tissue >100x higher than with oral dosing

• No additive effect of Dual

• TFV-DP ~5-15% of TFV in the same compartment

• Effective concentrations have not been establishedLo

g1

0 T

FV &

TFV

-DP (

fmol/m

g o

r p

mol/m

L**)

Serum TFV Cmax

PBMC TFV-DP Cmax

CVL TFV

Endocervical

Cytobrush TFV-DP

Tissue TFV-DP

Tissue TFV

*Median <LLOQ, assigned BLQ/2 for median; value **Molar equivalent units assumptions: gm = mL, 106 cells = 0.2uL

**

0 0 0

**

*1 42 30 0 71 1 56 4 3 52 3 2 34 5%BLQ

iPrEx: Number Needed to Treat Compared with

Other Health Interventions

Outcome of Interest Intervention

# Needed to Treat to Prevent Outcome

Death from colorectal cancer

Annual FOBT Colorectal Screen1 4,551

Stroke in women with no previous CV disease

Aspirin 81 mg daily2 411

Heart attack in hypertensives with average cholesterol

Atorvastatin 10 mg daily3

100

HIV infection in MSM Truvada 1 pill daily4 37

1 Mandel JS, Bond JH, Church TR. et al. Reducing mortality from colorectal cancer by screening for

fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328:1365

2 Berger, J.S. Et al. Aspirin for the primary prevention of cardiovascular events in women and

men: a sex-specific meta-analysisof randomized controlled trials. JAMA 2006; 295:

306-313. 3 PS Sever et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients

who have average or lower-than-average cholesterol concentrations, in the Anglo-

Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a multirandomised

trial. Lancet 2003; 361: 1149-1158. 4 Grant RM, Lama JR, Anderson PL, et al.

Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med

2010;363:2587-2599

1Mandel, et al. NEJM, 1993; 2Berger, et al. JAMA, 2006; 3Sever, et al. Lancet, 2003; 4Grant, et al. NEJM, 2010.

Cost-effectiveness for PrEP by efficacy, cost, age and HIV incidence

Paltiel A D et al. Clin Infect Dis. 2009;48:806-815

© 2009 by the Infectious Diseases Society of America

PrEP Bridges

To Better PlacesFrom To

Denial and stigma HIV test

Negative HIV Test Protective behavior

Multiple partners Intimacy

Serodiscordant couples Viral suppression on treatment

Stigma and Loss to Follow-up Retention in care

Don’t ask (about sex), don’t tell

Prevention for positives

“Treatment mortgage” with balloon payments

Fixed rate to fully fund universal test and treat

Robert Grant, April 2011

Collateral BenefitsAll observed during PrEP in iPrEx

• Found the epidemic with surveillance• Increased HIV testing and counseling• Timely identification of acute infections• Decreased partners• More condom use• Universal HBV vaccination• Routine STI screening and treatment• Antiretroviral treatment or linkage to care• Advocacy for state of the art therapy• 687 people employed • Advocacy for constitutional protections• Community building• Good Participatory Practices

Models Could Consider Collateral Benefits

Regulatory and Normative Status

of Oral FTC/TDF PrEP United States Gilead preparing supplemental

NDA Pre-submission meetings with FDA CDC issues interim guidance

Outside The United States “We are not ready” Looking to the US for examples

Robert Grant, April 2011

Will pill taking increase if people are given FTC/TDF (without placebo) and know it can be effective?

What will happen to sex practices?

Safety and acceptability of every 12 week visits

Collect more safety data over longer periods of time

Open Label Extension Aims:

• Stop Giving a Placebo

• Provide New Information •About Efficacy•About Safety

• Reassurance at week 4

• Decide to Use PrEP•Cohort benefits given to all

• “Next Step” Counseling•Client centered, motivational •Neutral Assessment•Focus on barriers and facilitators

• Monitor and Discuss Drug Levels

Strategiesfor Improving

PrEP Use

Intermittent PrEP AdherenceIAVI East African Trial

• 72 MSM and FSW in Kenya• 72 Discordant Couples in Uganda• Truvada vs. Placebo 2:1• Daily vs. twice weekly and post exposure (1:1)• MEMS data adjusted for curiosity openings

48

Regimen MSM/FSW% (IQR)

Couples% (IQR

Daily 92% (79-99%) 97 (93-100%)Non-daily Fixed Doses 55% (28-88%) 91% (77-98%)Post Exposure Doses 26% (14-50%) 45% (20-63%)

Mutua et al, Vienna, 2010

The ADAPT Study (HPTN 067)Alternative Dosing to Augment PrEP Pill Taking

• Intermittent PrEP in:–MSM (N = 180, Bangkok, Thailand)–WSM (N = 180 Cape Town, South Africa)

• Oral FTC/TDF in three dosage groups: –Daily dosing–Time-driven dosing group: FTC/TDF twice weekly with a post-exposure boost. –Event-driven dosing group: FTC/TDF before and after a potential exposure to HIV infection.

• Drug Level in Hair and PBMC

An Opportunity to Win the War Against HIVStop Spread to Let Treatment Catch Up

Many new opportunities, a moment to invest

Exposure Intervention

Gestational Suppressive Therapy

Needle Clean Needles

Penile Male Circumcision

Vaginal TDF 1% Gel

Rectal Oral FTC/TDF

“Let’s Communicate”

maurice cook ( em designs group, inc.) a pill a day to keep hiv away robert m grant, april 28, 2011

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