Looking back, looking forward:

what we know and don’t know about oral PrEP and tenofovir gel for

preventing HIV in women

Jared Baeten MD PhDDepartments of Global Health and Medicine

University of WashingtonSatellite: CHOICE MATTERS: expanding the method mix of

ARV-based prevention for women in 2012 and beyond

Outline

What we knowWhat we’ve learned from clinical trials of oral and

topical tenofovir for HIV prevention in women What we don’t (yet) know

What can we answer in the short- and medium-term

What awaits usWhat are the next steps in the field

What we know

What we know

• Oral and topical tenofovir work for preventing HIV acquisition

Efficacy in PrEP trials

Study Population N Results

CAPRISA 004South Africa Women 889 39% efficacy vaginal TFV gel

iPrExBrazil, Ecuador, Peru, South

Africa, Thailand, USMSM 2499 44% efficacy FTC/TDF

TDF2 StudyBotswana

Young men and women 1200 62% efficacy FTC/TDF

Partners PrEP StudyKenya, Uganda

Heterosexual couples 4758 67% efficacy TDF

75% efficacy FTC/TDF

FDA review of Truvada® PrEP for HIV prevention

Deborah Birnkrant, director of the Division of Antiviral Products, US FDA, 16 July 2012

What we know

• Oral and topical tenofovir work for preventing HIV acquisition

• Adherence to oral/topical PrEP is key to HIV protection

CAPRISA 004: Adherence Efficacy

• High (>80% gel adherence) n=336 (38%)54% effective

• Intermediate (50-80% adherence) n=181 (20%) 38% effective

• Low (<50% gel adherence) n=367 (42%)28% effective

Abdool Karim et al, Science 2010

Adherence and HIV protection in oral PrEP trials

% of blood samples with

tenofovir detected

HIV protection efficacy in

randomized comparison

Partners PrEPFTC/TDF arm 81% 75%

TDF2 79% 62%

iPrEx 51% 44%

FEM-PrEP 26% 6%

There is a clear dose-response between evidence of PrEP use & efficacy

Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010Van Damme et al N Engl J Med 2012Thigpen et al N Engl J Med 2012

Tenofovir levels and HIV protection

• And when PrEP was taken (=detected in blood), protection was very high

% of non-seroconverters with tenofovir

detected in blood

HIV-1 relative risk reduction: detection

versus no detection of tenofovir

Protection p-value

iPrEx 51% 92% <0.001

Partners PrEPFTC/TDF arm 81% 90% 0.002Baeten et al N Engl J Med 2012

Grant et al N Engl J Med 2010

What we know

• Oral and topical tenofovir work for preventing HIV acquisition

• Adherence to oral/topical PrEP is key to HIV protection

• PrEP is not for everyone

CAPRISA 004 adherence

• High (>80% gel adherence) n=336 (38%)54% effective

• Intermediate (50-80% adherence) n=181 (20%) 38% effective

• Low (<50% gel adherence) n=367 (42%)28% effective

Abdool Karim et al, Science 2010

Tenofovir levels in trials

• In the clinical trials, not everyone took PrEP

% of non-seroconverters with tenofovir

detected in blood

HIV-1 relative risk reduction: detection

versus no detection of tenofovir

Protection p-value

iPrEx 51% 92% <0.001

Partners PrEPFTC/TDF arm 81% 90% 0.002Baeten et al N Engl J Med 2012

Grant et al N Engl J Med 2010

Sustained use (and non-use) of PrEP: Partners PrEP Study

At Month 1, ~80% had tenofovir detected

Donnell et al CROI 2012

Sustained use (and non-use) of PrEP : Partners PrEP Study

Those who had no tenofovir at Month 1 tended to have no

tenofovir throughout

Donnell et al CROI 2012

Sustained use (and non-use) of PrEP : Partners PrEP Study

Exception: pregnancies

Those who had tenofovir at Month 1 tended to have

tenofovir throughout

Donnell et al CROI 2012

What we don’t know (yet)

What we don’t know (yet)

• What motivates PrEP adherence (and how to motivate when not present)

What motivates PrEP use?

• Risk perception is a potentially powerful driver of adherence

• FEM-PrEP = young women • 70% perceived themselves to be at little or no HIV

risk, very low adherence

• Understanding interface of risk perception & HIV prevention is key for any strategy

What we don’t know (yet)

• What motivates PrEP adherence (and how to motivate when not present)

• The potential interface of biology, gender, adherence, and HIV protection

PrEP efficacy trial results in women

Study TFV gel TDF FTC/TDFCAPRISA 004

South Africa 39% efficacy

TDF2 StudyBotswana

49% efficacy / 75% as-treated

Partners PrEP StudyKenya, Uganda 71% efficacy 66% efficacy

FEM-PrEPKenya, South Africa,

Tanzania6% efficacy

VOICESouth Africa, Uganda,

ZimbabweFutility Futility Ongoing

FACTS 001South Africa Ongoing

Pharmacokinetics and PrEP adherence

• PK studies offered one possible mechanism for lower HIV protection in women: oral tenofovir results in >10x higher concentrations in rectal tissue than cervical and vaginal tissue.

Patterson et al. Sci Transl Med 2012

Rectal Vaginal Cervical0tan29a566029

0tan9a56609

0tan10a566010

0tan24a566224

0tan16a568716

Tissue tenofovir concentrations at 24 hours after a single dose of oral

FTC/TDF

Divergent PrEP trials: adherence + biology

Adherence

PrEP Efficacy

Biologymarginal vaginal concentrations,

inflammation, acute HIV in partner, etc. could make PrEP more sensitive to imperfect

adherence, particularly in women, which could have influenced some PrEP trial results

Tenofovir gel – does dosing matter?

• Two trials of tenofovir gel have conflicting results.

• Is there a benefit/toxicity balance to strike here, with daily use (VOICE) being “too much” and coital use (CAPRISA 004) favoring HIV-1 protection over toxicity?

Study CAPRISA 004 VOICE

Sample size 889 ~2000

Number of HIV events 98 Estimate ~90

Efficacy(95% CI)

39%(6-60%) ~0%

Intervention Gel with coitus Daily gel

What we don’t know (yet)

• What motivates PrEP adherence (and how to motivate when not present)

• The potential interface of biology, gender, adherence, and HIV protection

• Intermittent use

Adherence and perfection

• Imperfect, but still regular adherence, might still provide substantial HIV protection, although PrEP is still as a daily medication

Estimated HIV risk reduction (95% CI)

2 doses/week 76%(56-96%)

4 doses/week 96%(90->99%)

7 doses/week 99%(96->99%)

Anderson et al. CROI 2012

What awaits us

What awaits us

• Trial completion and analysis

Ongoing trials: 2012

Study Population Ongoing

Partners PrEP StudyKenya, Uganda

Heterosexual couples

Oral TDF vs.Oral FTC/TDF

VOICESouth Africa, Uganda, Zimbabwe Women Oral FTC/TDF vs.

placebo

Bangkok Tenofovir StudyThailand IDUs Oral TDF vs.

placebo

FACTS 001South Africa Women TFV gel vs.

placebo

What awaits us

• Trial completion and analysis

• Implementation science, demonstration projects

PrEP demonstration questions, 2012

Topic Question

Targeting Who to prioritize for PrEP? How to deliver?

Uptake Do those who might benefit most from PrEP want it?

Adherence Who takes PrEP? Do they take it often enough?

Sexual behavior PrEP use as relates to behavior?

Impact HIV incidence? Resistance? Costs?

What awaits us

• Trial completion and analysis

• Implementation science, demonstration projects

• More options, opportunities for choice

Gel Vaginal ring

Tenofovir is the first-generation prevention agent

Vaginal film InjectablePill

Landmark health research is a process of continued development.

Thank you