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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
6
• 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
Grant et al, CROI 2011
New England Journal of Medicine, online Nov 23, 2010
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
New England Journal of Medicine, online Nov 23, 2010
New England Journal of Medicine, online Nov 23, 2010
New England Journal of Medicine, online Nov 23, 2010
New England Journal of Medicine, online Nov 23, 2010
Nausea on History
New England Journal of Medicine, online Nov 23, 2010
Weight Gain
New England Journal of Medicine, online Nov 23, 2010
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
Grant et al, CROI 2011
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
28
30
Sexual Partners
New England Journal of Medicine, online Nov 23, 2010
Condom Use with High Risk Sex
New England Journal of Medicine, online Nov 23, 2010
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
35
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
Cost
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
51
“Let’s Communicate”