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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 Washington
Satellite: 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
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
475867% 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 2012Grant 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 2012Grant 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 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/TDF
CAPRISA 004South 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/week76%
(56-96%)
4 doses/week96%
(90->99%)
7 doses/week99%
(96->99%)
Anderson et al. CROI 2012
Ongoing trials: 2012
Study Population Ongoing
Partners PrEP StudyKenya, Uganda
Heterosexual couples
Oral TDF vs.Oral FTC/TDF
VOICESouth Africa, Uganda, Zimbabwe
WomenOral FTC/TDF vs.
placebo
Bangkok Tenofovir StudyThailand
IDUsOral TDF vs.
placebo
FACTS 001South Africa
WomenTFV gel vs.
placebo
PrEP demonstration questions, 2012
Topic Question
TargetingWho to prioritize for PrEP?
How to deliver?
UptakeDo those who might benefit most from
PrEP want it?
AdherenceWho 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.
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