CCTN and MPT Stakeholder
Round Table on Hormonal
Contraception (HC) in MPTs
20 May 2015
Rockville, Maryland
Welcome & Introductions
Diana Blithe (NICHD)
Bethany Young Holt (CAMI Health)
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
MPTs in the Pipeline

Drug combinations

Drug/Device
combinations

Multipurpose
injectables

Bacterial
therapeutics

Nanoparticles
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Initiative for MPTs (IMPT)
Contraception
Science
HIV
Prevention
Women’s Voices
& Access
STI
Prevention
Funder
Collaboration
Advocacy &
Market
Development
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
September 2014 – HC in MPTs
Meeting Objectives

Unite experts in contraception and MPT
development to discuss relevant contraceptive
research to help guide MPT development and
investment decisions.

Inform product developers and supporting
agencies about expert recommendations for
the use of hormonal contraception (HC) in MPT
products.

Discuss appropriate strategies for including HC
into MPT products between contraceptive
experts and MPT developers.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Objectives for the Day

Review gaps and challenges identified at the
September 2014 HC in MPTs meeting.

Review preliminary results of the online HC
and MPT prioritization survey.

Assess the status of CCTN member MPT
research in relation to priorities and gaps.

Discuss bleeding patterns and acceptability
associated with specific hormone
combinations and dosing regimens.

Discuss key questions that may help inform
successful MPT development and uptake.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
IMPT Priority Issues Survey on HC
in MPTs
Chairs: Diana Blithe (NICHD),
Bethany Young Holt (CAMI Health)
Discussants: All
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
IMPT Priority Issues Survey on HC in MPTs
Objective: Review gaps and challenges identified at
September 2014 HC in MPTs meeting and prioritize
activities for IMPT follow-up.

Format
– Likert scale ranking: High, Medium, Low, and
No Opinion
– Are you, or others you are aware of, actively
addressing this issues
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
IMPT Priority Issues for HC in MPTs
Q1. Systemic effects: Association of HC plasma levels and anovulation and
contraceptive efficacy (57.1%)
Q2. Topical effects: Systematic investigation of Mechanisms of Action (MoA) for
contraception other than ovulation (57.1%)
Q3. Data on HCs other than LNG suitable for MPTs (57.1%)
Q4. Contraceptive efficacy in women with high BMI through systemic or topical
MOA (14%)
Q5. Surrogate markers for effectiveness to determine PK and PD and interaction of
HC with other APIs. (57.1%)
Q6. Understanding relationship between bleeding and acceptability of HC options
(14%)
Q7. Role of Cytochrome P450 enzyme for drug metabolism for Pis and NNRTIs. (0%)
Q8. Beyond IVRs, development of on-demand and long-acting formulations for
MPTs combining HC and ART. (71.4%)
Q9. Novel robust acceptability and commercial feasibility measures for key MPT user
groups. (57.1%)
Q10. Other contraceptive research for the MPT field. (57.1%)
HC in MPTs Gaps/Challenges Survey
High Priority Areas

Q8. Beyond IVRs, development of on-demand
and long-acting formulations for MPTs
combining HC and ART.

Q3. Data on HCs other than LNG suitable for
MPTs

Q1. Systemic effects: Association of HC plasma
levels and anovulation and contraceptive
efficacy
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
HC in MPTs Gaps/Challenges Survey
High Priority Areas

Q2. Topical effects: Systematic investigation of Mechanisms of
Action (MoA) for contraception other than ovulation
– protection by:
• Cervical mucus
• Endometrial thickening, thinning, dilatation
• Uterine tubal junction (sperm entry)
• Inhibition of sperm function
• Other
– LNG to date the HC with most data?

Q5. Surrogate markers for effectiveness to determine PK and PD
and interaction of HC with other APIs.
– Pregnancy as main outcome measure historically
– To determine PK and PD and interaction with other APIs, new
markers and meaningful thresholds needed
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
HC in MPTs Gaps/Challenges Survey
High Priority Areas

Q9. Novel robust acceptability and
commercial feasibility measures for key MPT
user groups.

Q10. Other contraceptive research for the
MPT field.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
HC in MPTs Gaps/Challenges Survey
Lower Priority Areas

Q4. Contraceptive efficacy in women with
high BMI through systemic or topical MOA

Q6. Understanding relationship between
bleeding and acceptability of HC options
– Will discuss further in later session

Q7. Role of Cytochrome P450 enzyme for
drug metabolism for Pis and NNRTIs.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Status of Ongoing Work
Chair: Beatrice Chen (Magee-Womens Research Institute)
Discussants: Sharon Achilles (Magee-Womens Research
Institute), Annie Thurman (CONRAD), Phil Darney (UCSF)
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
Status of Ongoing Work

Objective: Assess the status of CCTN
member MPT research in relation to
identified research priorities and gaps.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Sharon Achilles, MD, PhD
UNIVERSITY OF
PITTSBURGH
Revisiting the IMPT Priority Issues for HC in MPTs
Q1. Systemic effects: Association of HC plasma levels and anovulation and contraceptive efficacy
Q2. Topical effects: Systematic investigation of Mechanisms of Action (MoA) for contraception
other than ovulation
Q3. Data on HCs other than LNG suitable for MPTs
Q4. Contraceptive efficacy in women with high BMI through systemic or topical MOA
Q5. Surrogate markers for effectiveness to determine PK and PD and interaction of HC with
other APIs.
Q6. Understanding relationship between bleeding and acceptability of HC options
Q7. Role of Cytochrome P450 enzyme for drug metabolism for PIs and NNRTIs.
Q8. Beyond IVRs, development of on-demand and long-acting formulations for MPTs combining
HC and ART.
Q9. Novel robust acceptability and commercial feasibility measures for key MPT user groups.
Q10. Other contraceptive research for the MPT field.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
DRUG-DRUG
INTERACTIONS
Q7. Role of Cytochrome P450 enzyme for drug
metabolism for PIs and NNRTIs.
Contraceptive Pharmacokinetics
COCs
DMPA
LNG-IUD
ENG-I
Vaginal Ring
[Serum Progestin] ng/mL
7
6
5
4
3
2
1
Contraceptive
efficacy
0
3mo 3yr
Achilles, SL. 2014
Background: WHO Antiretroviral
Therapy (ART) Recommendations
EFV = Efavirenz
NVP = Nevirapine
CYP3A4 inducers
CYP = cytochrome P450
Progestin
CYP3A4
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Progestin
Studies of Combined use of Contraceptive
Implants and NNRTI-based ART

6 cases of pregnancy with combined use of
the ENG implant and EFV1

Retrospective chart review of HIV+ women in
Swaziland using LNG implant (Jadelle):
• 15 (12.4%) of 121 women using EFV-based ART
became pregnant (no pregnancies with NVP)
 Mean time to pregnancy after implant
insertion was 16.4 months2
1Matiluko
A, et al. J Fam Plann Reprod Health Care. 2007;
McCarty EJ, et al. Int J STD AIDS. 2011;
Likhi N, et al. J Fam Plann Reprod Heath care. 2010;
Leticee N. et al. Contraception. 2011.
2Perry SH, et al. AIDS. 2014.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
•
PK study of EFV and ritonovirboosted lopinavir (LPV/r) and
ENG implant
• EFV – decreased ENG AUC by 63.4%
• LPV/r – increased ENG AUG by
52.0%
 LPV/r
 Control
 EFV
Vieira CS, et al. JAIDS. 2014
Results: PK Study of EFV
and LNG Implant
Control
group
(pg/mL)
NVP group
(pg/mL)
Week 1
1003
(702, 1286)
1326
(1073, 1579)
1.32
(1.22, 1.49)
462
(370, 553)
0.46
(0.43, 0.51)
Week 4
629
(496, 761)
866
(737, 995)
1.38
(1.31, 1.48)
349
(268, 429)
0.55
(0.54, 0.56)
Week 12
547
(433, 661)
758
(656, 860)
1.39
(1.30, 1.52)
326
(268, 286)
0.60
(0.58, 0.62)
Week 36
500
(394, 605)
679
(596, 709)
1.36
(1.30, 1.44)
280
(208, 353)
0.56
(0.53, 0.58)
Scarsi KK. International AIDS Society. 2015
NVP:Control EFV group EFV:control
GM Ratio
(pg/mL)
GM ratio
(90% CI)
(90% CI)
Unintended Pregnancies
with Jadelle
3 pregnancies observed in the EFV group
None in the control group or NVP group
Pregnancy 1 Pregnancy 2 Pregnancy 3
(pg/mL)
(pg/mL)
(pg/mL)
Over
Week
1 the 48 weeks
693 of combined
501LNG-EFV use
185
• LNG
were reduced
by 45-57%
Week
4 concentrations
631
411
201
• LNG AUC was reduced by 48%
Week 12
348
363
125
Week 24
297
268
150
Week 36
299
303
122
Scarsi K. CROI. 2015
A Pharmacokinetic Evaluation of the
Etonogestrel Implant and Non-Nucleoside
Reverse Transcriptase Inhibitor-Based
Antiretroviral Therapy in Ugandan Women
Catherine Chappell, MD MSc
Fellowship in Family Planning Annual Meeting
May 3, 2015
HIV+ women desiring an implant
Research Design
No ART (Control)
(13/20 participants)
6 months (ENG)
NVP-based ART
(20/20 participants)
Implant
EFV-based ART
(17/20 participants)
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
HORMONE
CONCENTRATIONS
Q1. Systemic effects: Association of HC plasma levels and
anovulation and contraceptive efficacy
Q2. Topical effects: Systematic investigation of
Mechanisms of Action (MoA) for contraception other than
ovulation
Q3. Data on HCs other than LNG suitable for MPTs
Contraceptive Hormone Induced Changes
(CHIC)

Two “sister” studies
– CHIC-II (Pittsburgh, PA, USA)
– Zim CHIC (Harare, Zimbabwe)

Evaluation before and after initiation of
HC
–
–
–
–
immune cell populations (systemic and genital)
microbiota
innate immune factors
Contraceptive hormone concentrations in
blood and genital tract
Round Table on HC in MPTs
20 May 2015 – Rockville, MD





Sister Studies Designed to Understand Immunologic,
Biomic and Inflammatory Impacts of Contraceptive Use
CHIC-II (Pittsburgh,
 Zim CHIC (Harare,
PA)
Zim)
Funded by NIAID
 Funded by BMGF
(04/2012)
(09/2012)
US population
 Sub-Saharan
population
Low HIV prevalence
area
 High HIV prevalence
area
Contraceptives:
– DMPA (MPA inject)
 Contraceptives:
–
–
–
–
–
ENG-I (ENG implant)
Cu-IUD (IUD-no hormone)
COCs (oral LNG+E2)
LNG-IUD (LNG IUD)
Control (no hormone)
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
–
–
–
–
–
–
DMPA (MPA inject)
ENG-I (ENG implant)
Cu-IUD (IUD-no hormone)
MPA/E2 (MPA inject+E2)
Net-En (norethisterone inject)
LNG-I (LNG implant)
Study design
Prospective parallel cohort studies
 Given individual variation in endpoints

– Normally cycling women without exogenous
hormone use are enrolled in follicular phase
• baseline samples collected
• Initiated on contraceptive
– Follow-up visits at 1*, 3, and 6 months
• Repeat sample collection at each visit and results
compared to baseline to assess individual change
• Women serve as own controls to eliminate individual
variation
*Zim CHIC only
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Current Participants by Method
As of May 14, 2015
Zim
CHIC
CHIC
II
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Serum Hormone Assays
Pre-planned serum hormone assessment
 Collaborative effort with the Small Molecule Biomarker
Core to develop liquid chromotography/tandem mass
spectrometry (UPLC-MS/MS) assays
– Estrogen: estradiol and ethinyl estradiol
– Progestogen: progesterone, LNG, ENG, norethindrone,
MPA
• Panels developed and validated for blood and CVL
• Immunoassays are simpler but
– cross-reactivity with structurally similar metabolites->
decreased specificity
– Inability to measure multiple analytes simultaneously

Round Table on HC in MPTs
20 May 2015 – Rockville, MD
UPLC/MS/MS for Quantification

Advantages
– Multiple analytes simultaneously
– Highly sensitive and SPECIFIC method
– Linearity of calibration curves for more
accurate quantification
– Good inter-day reproducibility

Disadvantages
– More expensive than typical immunoassays
– More time intensive than immunoassays
– Need parent compound and Ideally requires
a deuterated (d3 or greater) of the analyte
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Plasma Progestin Concentrations
30, 90, and 180 days
after Initiation of Use
1500
1000
500
Contraceptive
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
-I
G
EN
LN
G
-I
N
-E
et
N
M
PA
/E
2
0
D
M
PA
Median pg/mL
2000
More data coming soon…
Increased numbers from the Zimbabwe
cohorts
• Starting soon UPLC/MS/MS testing of
Pittsburgh cohorts
•
•
•
•
•
•
LNG-based COCs
DMPA
LNG-IUD
ENG-I
Vaginal hormone concentrations from
Zimbabwe and Pittsburgh cohorts
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
MTN-030/IPM 041
MTN-IPM RING
COLLABORATION
Q1. Systemic effects: Association of HC plasma levels and
anovulation and contraceptive efficacy
Q2. Topical effects: Systematic investigation of
Mechanisms of Action (MoA) for contraception other
than ovulation
Key Product Characteristics
•
Matrix ring of the same dimensions
as the Dapivirine Vaginal Ring
•
Silicone Polymer: Pt-catalysed
(addition-cured)
•
Developed for 90-days of use
•
Stable for at least 36 months for
SSA environment
Slide courtesy of J. Holt
Levonorgestrel Dose??
What is the goal?
 Load of drug in the ring
 Amount of drug delivered by the ring
– Dependent on the load and the in vivo release
rate
Plasma drug levels achieved
 Local drug levels achieved
 Contraceptive efficacy!

Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Levonorgestrel Dose??
•
Multiple components considered
o Extrapolation from literature on vaginal PK in
women
(Landgren ‘85, ’86, ’94; Brache ’07, Sitruk-Ware ‘09,’09; Kives ‘05; Devoto ‘05)
o In vitro release rates in high solvent
(IPA:water) and “physiologic” (acetate
buffer/solutol) conditions
o Sheep PK –does not appear predictive for
human PK
o Limited CHIC data available to date
Slide courtesy of J. Holt
Effective Levonorgestrel
Concentration in Plasma

Pharmacokinetic targets derived from
literature
– Low dose: > 250 pg/mL in plasma
– High dose: > 1000 pg/mL in plasma
– Steady state in COC users ~2000 pg/mL
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
MTN-030/IPM 041

PK Study of Vaginal Rings Containing Dapivirine
and Levonorgestrel used for 90 days
– Dapivirine 200mg ring
– Dapivirine 200mg/LNG 32mg ring
– Dapivirine 200mg/LNG 320mg ring

Randomized 6 women per group (N=18 total)
– 3 women of BMI <30 and 3 women of BMI 30-35/group
– Sampling: 24h, 48h, 72h, 7d, 14d, 21d, 28d, 60d and 90d

Serum & vaginal drug levels

What is the lowest acceptable LNG
concentration? 200pg/mL? 250pg/mL?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
CCTN and MPT Stakeholder Round Table
HCs and MPTs
Bethesda, MD
May 20, 2015
Multipurpose
Intravaginal Ring:
Tenofovir / Levonorgestrel
Andrea Thurman, MD
Highlights
• CONRAD tenofovir/levonorgestrel ring:
– Choice of LNG
– Ring design
– Preclinical testing
– Clinical study design
Use of Levonorgestrel
• Synthetic progestin used in many contraceptives:
Systemic
Oral
Implant
LNG-only
LNG + estrogen
Daily “mini-pill” 0.03 mg
Emergency contraception
Daily combined pill
Emergency contraception
Pericoital pill
Norplant
Jadelle
Sino-Implant
Transdermal
Genital tract
Intrauterine
Intravaginal
LNG patch
LNG + ethinyl estradiol patch
Mirena IUS – 20 µg/day
Skyla IUS – 14 µg/day
LNG ring - 20 µg/day
LNG + estradiol ring
LNG/carraguard Gel
(Bold = commercially available. Others investigational or discontinued)
Use of Levonorgestrel
• Synthetic progestin used in many contraceptives:
Systemic
Oral
Implant
LNG-only
LNG + estrogen
Daily “mini-pill”
Emergency contraception
Daily combined pill
Emergency contraception
Pericoital pill
Norplant
Jadelle
Sino-Implant
Transdermal
Genital tract
Intrauterine
Intravaginal
LNG patch
LNG + ethinyl estradiol patch
Mirena IUS – 20 µg/day
Skyla IUS – 14 µg/day
LNG ring - 20 µg/day
LNG + estradiol ring
LNG/carraguard Gel
(Bold = commercially available. Others investigational or discontinued)
Systemic vs
genital delivery of LNG
• Genital delivery  lower plasma levels and
higher genital tract levels1
• Distribution beyond endometrium facilitated
by large uterine, vaginal arteries
anastomoses2
• Genital tract effects from genital delivery may
differ from those seen after systemic delivery
1Devoto
2005 Fertil Steril 84(1):46-51
2Lete 2010 Curr Drug Met 11:839-49
Suppression of ovulation
Greater chance
of irregular
bleeding
• No development of the ovarian follicle (and
therefore no ovulation)
• Some follicular development but no ovulation
and no increase in progesterone
• Follicular development with luteinized
unruptured follicle and progesterone
production
• Normal ovulation
Less chance of
ovulation
• Complete suppression of ovulation not needed for a
contraceptive effect.
• Alterations in endocrine profile can provide contraception while
maintaining normal bleeding patterns:
• If ovulation does occur, changes in cervical mucus prevent
pregnancy
Complete suppression of ovulation not
needed for contraception
• Mirena:
– Mirena: ~50% of cycles are ovulatory in the 1st
year, and about 75% in the 4th year, but
pregnancy rate is 0.7% over 5 years
• Norplant:
– 20% of cycles are ovulatory in the 1st year, and
50% in the 5th year, but still contraceptive
LNG’s effect on Cervical Mucus
• Cervical mucus protects uterine cavity from pathogens; controls sperm
migration
• Before ovulation:  Estrogen   secretion and  water  easier sperm
migration
• “Quality” assessed via volume, viscosity, spreadability (Spinnbarkeit),
crystallization pattern (ferning), and cellularity
– Score of ≥ 10 out of 15 considered “good”
• Even in ovulatory cycles, LNG  thick mucus with poor sperm penetration
– Happens quickly:
• Norplant: 3 days after insertion, sperm penetration becomes poor despite high
estradiol levels1
• Mirena users: Cervical mucus becomes poor in 7 out of 10 one day after insertion, in
10 out of 10 by third day2
– Effect is profound:
• In Mirena 20 µg users, no sperm migration despite ovulation3
• LNG 20 µg ring: Inhibition of sperm migration in 92% of post-coital tests4
– Happens at low dose
• Seen with lower LNG dose in IUS – Skyla (14 µg)5
1 Dunson
1998 Fertil Steril 69: 258-66 2Natavio 2012 Contraception 87(4):426-31 3Lewis 2010 Contraception 82(6):491-6 4WHO J
Steroid Biochem 1979;11(1B): 461-467 5 Apter 2014 Fert Ster 101(6):1656-62
Efficacy of 20 µg LNG ring
shown in 2 trials
• Efficacy of silicone ring releasing 20 µg/day studied in 1980s:
– 90-day ring used for 1 – 2 years
– WHO study (n = 1005)
• Pregnancy rate at 1 year: 3.5 per 100 women (95% CI 2.2-5.0)
– UK study (n = 1591)
• Pregnancy rate:
– At 1 year: 5.1 per 100 women (95% CI 3.6-6.6)
– At 2 years: 6.5 per 100 women (95% CI 4.4-8.6)
– Within range of other user-controlled hormonal methods
• Suppression of ovulation correlated with irregular bleeding
among ring users
– # days with bleeding and spotting significantly higher in segments with suppressed
ovulation vs normal ovulation1
• Development discontinued until now
1Landgren
et al Contraception 1982 26(6): 567-585.
The CONRAD TFV/LNG ring:
Design challenges
• Goal: meet 2 target release profiles not achieved using any
other ring platform:
– Approximately 10 mg/d TFV for ≥ 90 days
– 20 µg/d LNG for ≥ 90 days
• Challenges:
1) Release 2 very different drugs
• TFV: hydrophilic, poorly released from traditional silicone or EVA rings
• LNG: hydrophobic
2) At very different rates
• TFV: about 10 milligrams/day
•
Requires high drug loading (>1 gram TFV in a 4.5 gram ring)
• LNG: 20 micrograms/day
3) At a steady rate over time (zero order) for ≥ 90 days
The CONRAD TFV/LNG Ring: Solutions
•
•
Developed in collaboration with Patrick Kiser, Northwestern University
Polyurethane reservoir rings:
– Using commercially available biomedical grade polyurethanes that range from hydrophilic
to hydrophobic
• Suitable for 2 different drugs using 2 different
segments, releasing at 2 different rates:
• TFV segment:
• Hollow-core reservoir using hydrophilic
polyurethane
• High loading capacity and rate of release
• LNG segment:
• Solid-core reservoir using hydrophobic
polyurethane
• Similar to NuvaRing (EVA) design
• Result: tightly controlled steady release for long
duration
• Suitable for one or more drugs (similar or
diverse)
Clark et al, PLoS ONE (2014) 9: e88509
The CONRAD TFV/LNG ring:
In vitro target release profiles met
Clark 2014 PLoS ONE 9(3):e88509
The CONRAD TFV/LNG ring:
Animal PK studies, TFV
Sheep
Pigtail Macaques
Vaginal fluid
Vaginal fluid
Vaginal tissue
Vaginal tissue
Plasma
Plasma
 Median TFV-DP in macaque vaginal tissue: 1.7-7.4x104 fmol/mg
 Time-independent TFV release from ring. Median levels similar to gel.
Johnson et al, AAC 2012 (56): 6272-83; Moss et al, AAC 2012 (56):5952-5960
Ongoing CONRAD study
• First multipurpose ring in clinical trials:
– Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and
Acceptability Study of Intravaginal Rings Releasing Tenofovir and
Levonorgestrel or Tenofovir Alone (Protocol A13-128)
• 100 women consented to complete 50 across 2 sites:
– Eastern Virginia Medical School, Norfolk, VA: Annie Thurman, PI
– Profamilia, Santo Domingo, Dominican Republic: Vivian Brache, PI
• 3 treatment groups, randomized 2:2:1
– TFV-only ring (n=20)
– TFV/LNG ring (n=20)
– Placebo ring (n=10)
• About 1 month of 90-day ring use, total 3 months participation
• 8 or 9 visits and 1 follow-up contact
Objectives
• Primary:
– Genital and systemic safety
• Secondary:
– Pharmacokinetics (PK) of LNG and TFV
• Tertiary:
– Pharmacodynamics (PD) of LNG and TFV
– Acceptability
Selected entry criteria
• Ovulatory baseline cycle (progesterone ≥3 ng/ml)
• Protected from pregnancy by one of the following nonhormonal methods:
– Sterilization of either partner
– Willing to abstain from vaginal intercourse
• BMI <30 kg
• May not use drugs that affect CYP3A4
Overall study design
Screening/
Enrollment
Pre-treatment
cycle to
document
ovulation
Ring in place
After ring removal
Relationship of ring days to
cycle days
Screening/
Enrollment
Visit #
Ring Day
Cycle
Day
Visit 1
Pre-treatment
cycle to
document
ovulation
Visit 2
Visit 3
Ring in place
After ring removal
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Ring
insertion
(24 hrs after
Visit 4)
At
ovulation*
Ring
removal
(24 hrs after
Visit 7)
(72 hrs after
Visit 7)
NA
~ -14
~ -10
1
2
~8
~16-18
~17-19
~19-21
Any day
21
24
7
8
~14
~22-24
~23-25
~25-27
• As determined by ovulation predictor kit.
• Expect to see greatest effects of LNG at Visit 6:
• Less favorable cervical mucus and poorer sperm migration
Safety endpoints
Visit #
Visit 4
Visit 5
Ring insertion
(24 hrs
after Visit 4)
At ovulation
Ring removal
8
2
~14
~8
(8-10 days after Visit
6)
~22-24
~16-18
Cycle Day
Ring Day
Soluble immune mediators in
CVL
Microflora
Tissue:

Histology*

Epithelial integrity*

Target cell
phenotype/activation
status

Markers of mucosal
inflammation (gene
expression)
Microbial growth on and in
returned rings
Serum chemistries, CBC, lipids
7
1
Colposcopy
AEs


* = EVMS only
Ring in place
Visit 6
Visit 7
After ring removal
Visit 8
Visit 9
(24 hrs after
Visit 7)
(72 hrs after
Visit 7)
~23-25
~17-19
~25-27
~19-21













TFV and LNG PK endpoints
Visit #
Visit 4
Ring insertion
Cycle Day
Ring Day
TFV & LNG in blood
TFV in genital fluids
(aspirates, swabs)
TFV & TFV-DP in tissue
LNG in genital fluids
(swabs)
LNG in cervical mucus
Amount of drug in returned
rings
Ring in place
Visit 5
Visit 6
(24 hrs after
Visit 4)
At ovulation
7
1
8
2
~14
~8

(1, 2, 4, & 8 hrs)



(1, 2, 4, or 8 hrs)


Visit 7
Ring removal
(24 hrs after
Visit 7)
(72 hrs after
Visit 7)
~22-24
~16-18

Also TFV-DP in
PBMCs
~23-25
~17-19
~25-27
~19-21



½
(8-10 days after
Visit 6)

After ring removal
Visit 8
Visit 9





½
LNG PD endpoints
Visit #
Cycle Day
Ring Day
Cervical mucus: quality
and sperm migration
Blood: estradiol
(follicular development)
Visit 4
Ring in place
Visit 5
Visit 6
Ring
insertion
(24 hrs after
At
Visit 4)
ovulation
7
1
8
2
~14
~8
Visit 7
Ring removal
(8-10 days
after Visit 6)
~22-24
~16-18



Blood: progesterone
(ovulation)

Endometrium:
thickness and histology
(latter EVMS only)

After ring removal
Visit 8
Visit 9
(24 hrs after (72 hrs after
Visit 7)
Visit 7)
~23-25
~17-19
~25-27
~19-21
TFV PD endpoints
Ring in place
Visit #
Visit 4
Ring
insertion
Visit 5
Visit 6
After ring removal
Visit 7
Visit 8
Visit 9
(24 hrs after
At
Ring removal (24 hrs after (72 hrs after
Visit 4)
ovulation (8-10 days
Visit 7)
Visit 7)
after Visit 6)
Cycle Day
7
8
~14
~22-24
~23-25
~25-27
Ring Day
1
2
~8
~16-18
~17-19
~19-21
Anti-HIV & anti-HSV
in genital fluid

Anti-HIV activity in
explants (EVMS only)

Study status
• As of March 13, 2015:
– Participants enrolled: 59
– Participants completed (goal 50): 25
• Interim analysis underway:
– To obtain early indication of ring performance:
• TFV and LNG PK
• LNG PD
• TFV PD (explants)
– Results expected in mid-May 2015
• Estimated date of last participant visit: January 2016
• Data available Q2 2016
Challenges
• Ring design:
– Sustained release for 90 days of 2 very
different drugs at 2 very different rates, that
would meet our preclinical benchmarks
• Study design:
– Assessing PK and PD of 2 different drugs
– Example: Visit 7 (ring removal)
– 10 specimens collected (including 5
cervicovaginal biopsies and 1 endometrial
biopsy) and sent to 7 labs
– Transvaginal ultrasound
– Colposcopy
– Multiple procedures on removed ring
• Regulatory approach:
– 2 indications
– 2 INDs
Acknowledgements
A Novel Multi-purpose Technology:
ARV and Progestin-eluting Cervical Cap
MPT Roundtable, 20 May, 2015, NICHD
Philip D. Darney, MD, MSc
Distinguished Professor
Obstetrics, Gynecology
and Reproductive Sciences
67
Global Problem
 Unintended pregnancies and HIV infection are the leading causes of
death in women of reproductive age globally.
 The contribution of unintended pregnancy to female mortality, along
with the devastating consequences of the HIV epidemic to women of
reproductive age, urges a convergence in pregnancy and HIV
prevention.
 Drug eluting rings do not protect the cervix to augment HIV and
pregnancy prevention
 Gel microbicide compounds limit compliance
Proposed Solution
Utilize approved, disposable cervical barrier cap to develop
an extended use, discrete, safe, comfortable, women
controlled means of contraception and HIV protection
Cervical Barrier Cap
 Annular ring of polymers
integrated into proprietary cervical
barrier cap for pregnancy
prevention and HIV protection.
 Levonorgestrel and a dual
antiretroviral compound,
Tenofovir to elude in a controlled,
time released manner.
 UCSF expertise in elution of
compounds from polymers
incorporated into stents or rings
San Francisco General Hospital
University of California, San Francisco
THANK YOU, philip.darney@ucsf.edu
UCSF Bixby Center for Global Reproductive Health
Revisiting the IMPT Priority Issues
Chairs: Diana Blithe (NICHD),
Bethany Young Holt (CAMI Health)
Discussants: All
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
IMPT Priority Issues for HC in MPTs
Q1. Systemic effects: Association of HC plasma levels and anovulation and
contraceptive efficacy (57.1%)
Q2. Topical effects: Systematic investigation of Mechanisms of Action (MoA) for
contraception other than ovulation (57.1%)
Q3. Data on HCs other than LNG suitable for MPTs (57.1%)
Q4. Contraceptive efficacy in women with high BMI through systemic or topical
MOA (14%)
Q5. Surrogate markers for effectiveness to determine PK and PD and interaction of
HC with other APIs. (57.1%)
Q6. Understanding relationship between bleeding and acceptability of HC options
(14%)
Q7. Role of Cytochrome P450 enzyme for drug metabolism for Pis and NNRTIs. (0%)
Q8. Beyond IVRs, development of on-demand and long-acting formulations for
MPTs combining HC and ART. (71.4%)
Q9. Novel robust acceptability and commercial feasibility measures for key MPT user
groups. (57.1%)
Q10. Other contraceptive research for the MPT field. (57.1%)
Bleeding patterns: Perspectives
Relevant to MPT Development
Chair: Alicia Christy (NICHD)
Discussants: Cynthia Woodsong (IPM),
Betsy Tolley (FHI 360), Diana Green Foster (UCSF)
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
Bleeding patterns:
Perspectives relevant to MPT development

Objective: Address biological and
social-behavioral questions related to
bleeding patterns for HC in MPTs.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Review of Literature
Cynthia Woodsong (IPM)
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
Relevant Literature

Microbicide acceptability & adherence
– Clinical trials, hypothetical (non-use) studies

Contraceptive preferences &
discontinuation

Menstrual practices, preferences, beliefs

Research methods for collecting data on
these topics
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Relevant “social and behavioral”
Literature



Microbicide acceptability &
adherence
Cross-cultural
Contraceptive preferences &
differences
discontinuation
throughout
Menstrual practices, preferences, these issues.
beliefs

Counseling

Research methods for collecting
data on these topics
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Microbicide acceptability &
adherence

Clinical trials & hypothetical (non-use)
studies
– Non-adherence is common in trials, &
frequently due to concerns about side
effects


Clinical trial participants are required to be
using highly effective contraceptive
Most data
methods; a large number of participants
• from subdo not have menses; pregnancies and
Saharan Africa
method switching may provide relevant
& U.S.
data
Vaginal ring (Africa): most common reason
for removal is menses-related (e.g., doesn’t
want to wear during menses, wants to
clean the ring after menses)
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
• focus largely
on vaginal gels
Contraceptive preferences &
discontinuation

Highest increase in uptake has been for
injectables, but this method also has highest
rates of discontinuation

Menses disruption is biggest reason for
method-related discontinuation

Preferences for high contraceptive efficacy may be
tempered by tolerance for side effects (use the “least
worst” method)

Acceptability is positively correlated with adherence

Individuals’ perceptions and reactions to their physical
responses to contraceptive products are highly variable
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Menstrual practices, preferences,
beliefs

Cross-cultural differences in views on importance of menses
–
–
–
–
–

Menses is natural/normal/healthy
Menses cleanses the uterus/vagina
Menses indicates woman is not pregnant
Menses is “God’s will”
Taboos & contamination beliefs
Preferences for menses
– Variability in preferences: Menses can be inconvenient, costly,
uncomfortable/PMS, male partner issues, etc. Some women prefer to not
have menses for these reasons.
– African women may be less accepting of amenorrhea

Practices for menses management, and sex during menses
– vaginal practices during and after menses (includes microbicide trial data);
scant data available on sex during menses indicates no/little sex (especially
in sub-Saharan Africa)

Adolescents
– Concerns about “normal,” lack of information/education about menses,
schoolgirls’ privacy/hygiene
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Counseling

Cochrane review (2014) indicates little clear
evidence for best counseling to improve
contraceptive adherence
– Intensive counseling plus reminders show
promise

Clinical trial counseling often stresses unknown safety &
efficacy of study products, which may affect adherence

General consensus is that women need clear information
about
– what to expect for bleeding disruptions
– duration of bleeding effects and long-term effects
– reproductive system basics
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Research methods







Settings: clinical trials, service delivery, general
population – impact findings
Definitions/measurement of bleeding
– menses, spotting, “normal,” time periods, volume
– self-report in interviews, diaries
Quantitative
– Scales & Questionnaires (e.g., Menstrual Attitudes Q.,
Menstrual Experiences and Behaviors Q., Menstrual
Education and Preparedness Q.)
Qualitative
– Interviews, Focus groups, photo-voice, body imaging,
etc.
Mixed methods
Translation issues (slang, metaphors, etc.)
Social desirability bias
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Factors impacting acceptability
research gaps
Diana Foster Greene (UCSF)
Round Table on HCs in MPTs – 20 May 2015 – Rockville, MD
Features of contraceptive methods
Stopping the method
I can stop using the method at any time.
I can get pregnant immediately after I stop using it.
Using the method
The method is easy to use.
I don’t have to remember to use the method each time I have sex.
I use the method only when I have sex.
Getting the method
The method is easy for me to get.
The method is affordable.
I can get the method without seeing a doctor or going to a clinic.
Side effects and health concerns
The method has few or no side effects.
The method doesn’t detract from my sexual enjoyment.
The method doesn’t detract from my partner’s sexual enjoyment.
The method has a health benefit.
The method protects against STI’s.
The method does not change my menstrual periods.
The method is very effective at preventing pregnancy.
Control and Privacy
I am responsible for using the method and not my partner.
I have control over when and whether to use method.
No one can tell that I’m using the method.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Percentage of women saying
this feature is very
Contraceptive
important
Features
The method is very effective at preventing pregnancy.
The method has few or no side effects.
The method is affordable
The method is easy for me to get.
The method is easy to use.
I have control over when and whether to use method.
I am responsible for using the method and not my partner.
I don’t have to remember to use the method each time I have sex.
The method doesn’t detract from my sexual enjoyment.
The method doesn’t detract from my partner’s sexual enjoyment.
The method protects against STI’s.
No one can tell that I’m using the method.
The method has a health benefit.
The method does not change my menstrual periods.
I can stop using the method at any time.
I can get pregnant immediately after I stop using it.
I can get the method without seeing a doctor or going to a clinic.
I use the method only when I have sex.
total
85%
79%
77%
76%
74%
71%
70%
66%
65%
62%
62%
58%
57%
52%
51%
51%
44%
36%
UI likely in > 3 UI in
next three previous 3
months
months
71%
70%
61%
63%
63%
73%
56%
54%
54%
Percent of features matched:
Once and future MOC
no method
over the counter pill
over the counter pericoital pill
ring
sponge
EC
pericoital pill
diaphragm
patch
self removable IUD
pills
IUD
shot
implant
steriliz ation
condom
withdrawal
71%
71%
68%
67%
67%
66%
64%
63%
62%
61%
60%
56%
51%
51%
51%
49%
37%
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
For 90% of women there is no
contraceptive method that has
all the features they think are
“extremely important”
Strategies to increase acceptability
of bleeding patterns for MPTs
Betsy Tolley (FHI 360)
Round Table on HCs in MPTs – 20 May 2015 – Rockville, MD
Overview

Strategies to increase acceptability
of bleeding patterns for MPTs
– Clinic Level Strategies
– Shaping Preferences

Research Gaps
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Provider-Client Disconnect


Providers
Prescribe methods that fit
perceptions of client needs
& abilities
Focus on medical info on SEs
versus experience of SEs
– Amenorrhea reduces anemia
– Break-through bleeding is not
menses


May provide inaccurate or
incomplete information
about method-related
menstrual SEs
Some hold similar
misperceptions about
menstrual SEs


Clients
Have little understanding of
how methods would fit
their needs
Have misperceptions
– Non-pregnancy amenorrhea
unhealthy, linked to infertility
or cancer or vaginal dryness

Worry about “clusters” of
SEs
– Long RTF explained by too
little or too much bleeding,
other SEs

Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Focus on how SEs impact
lifestyle, rather than
medical info
– Prolonged spotting disrupts
normal routines
Counseling Strategies

Structured information about DMPA, including
information on hormonal effects, shown to increase
continuation and effectiveness compared to routine
counseling
– De Cetina 2001 (350 Mexican women randomly assigned to structured versus
routine)
– Halpern Cochrane Review

Women in OC RCT evaluating continuous versus cyclic
use preferred the method they were randomized to
use.

Counseling should:
– Identify and address user questions and concerns
– Describe the range of possible menstrual (and other) changes
– Consider how bleeding and other SEs will influence women’s
lifestyles and relationships
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Management of Menstrual Changes

Waiting for women to return to the clinic may be too
late
– Egypt study, DMPA users with concerns about their method
reported seeing private doctors, rather than returning to the
FP clinic
Simply-worded but detailed information about side
effects may be sufficient
 Simple treatments for some hormonal side effects may
ease concerns

– COCs and estrogen-only treatments
– Non-steroidal anti-inflammatory drugs (NSAIDS)
Over-the-counter products to manage bleeding like
menstrual pads may help (but not always accessible)
 Other methods to verify non-pregnancy when
amenorrheic

Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Shaping Preferences

Persuasive messages have a specific behavioral
objective and are tailored to needs and concerns of a
specific audience
– Message must be salient to target group
– Channels for information dissemination will also vary
– Using multiple channels and targeting primary audiences and
those who influence them increases effectiveness

Messages
– Amenorrhea acceptable during pregnancy and expected after
menopause, but how to communicate its health benefits during other
life stages?
– How to delink amenorrhea from infertility?*
– How to communicate about patterns that change over time?

Channels
– Mobile phones and social media
– Mass media formats
– Interpersonal communications

How to target men?
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
Research Gaps

Understanding how to best counsel about
menstrual changes related to different methods:
– i.e., What is the relative effect of providing “structured
information” on menstrual effects versus “client-centered
questions” on method continuation?


Determining how to best support management of
menstrual side effects: counseling vs medical
treatment vs other management
Identifying best channels and messages to
enhance/shape provider and user acceptability of
method-included menstrual changes
– These will vary by audience (age, lifestyle and stage of life,
geographic setting, method)
Round Table on HCs in MPTs
20 May 2015 – Rockville, MD
MPT Stakeholder Questions &
Discussion
Chair: Joe Romano (NWJ Group/ IMPT Senior
Scientific Advisor)
Discussants: Jim Turpin (NIAID), other
Round Table on HC in MPTs – 20 May 2015 – Rockville, MD
MPT Stakeholder Questions & Discussion

Objectives:
– Provide overview of DAIDS research
program to members of the CCTN
– Obtain input from CCTN members on HC
and MPT relevant questions from MPT
Stakeholders (funders, product
developers)
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
CCTN and MPT Stakeholder
Roundtable on HCs and
MPTs
Jim A. Turpin, Ph.D., Chief
Preclinical Microbicides and Prevention
Research Branch (PMPRB)
Prevention Sciences Program
Division of AIDS
NIAID/NIH
May 20, 2015
Purpose of Presentation
Provide an overview of PMPRB’s research portfolio involving
hormonal contraceptives
Agenda:
1. Rationale for and focus of PMPRB’s portfolio involving
hormonal contraceptives
2. Summary of funded grants---No data since ongoing grants
The views expressed are those of the presenter and do not necessarily
reflect the official policies of the Department of Health and Human
Services (HHS), nor does mention of trade names, commercial
practices, or organizations imply endorsement by the U.S. Government
PMPRB’s Focus
Charged with preclinical discovery, development and early
clinical testing of non-vaccine biomedical prevention
strategies: topical microbicides, topical and systemic PrEP and
MPTs.
PMPRB Approach
Objective:
Development of a sustainable and effective non-vaccine
biomedical prevention pipeline of strategies (topical
microbicides, topical and systemic PrEP and MPTs).
The Problem:
Achieving the Objective requires not only drug development,
but also an understanding of the complexity of the male and
female genital and GI tract physiology and biology, and how
these factors impact susceptibility to HIV infection, and safety
and efficacy of the prevention products and their delivery
vehicles.
Critical Question:
What are the effects of endogenous and exogenous factors on HIV
susceptibility, and what product/strategy adjustments are needed to
sustain the safety and efficacy of clinically successful prevention
strategies following licensure?
HIV Susceptibility
HIV susceptibility is
controlled by multiple
factors which in
aggregate determine the
overall degree of
susceptibility to infection
Defining the HIV Infection Susceptibility Gap
Development of effective and safe global use prevention strategies must be
informed by the biology and physiology of the male and female genital and GI
tracts.
1. Role of the life cycle in HIV susceptibility.
How does age and maturation of the genital and GI system and tissues influence HIV
susceptibility?
2. Role of the immune system and inflammation in HIV susceptibility.
How do the adaptive and innate immune systems control resistance and
susceptibility to HIV infection?
3. Role of the microbiome and its impact on HIV susceptibility.
What is the role of the microbiome in product safety and efficacy?
4. Role of genital secretions and hormones (endogenous and exogenous) in HIV
susceptibility.
What is the relationship between endogenous and exogenous factors expression and
the safety and efficacy of prevention products and their delivery systems?
5. Role of tissue responses to prevention agents and their vehicles on HIV susceptibility.
How do drug and vehicle alterations in target cell homing, activation, inflammation,
innate and adaptive immunity and drug PK/PD/metabolism control susceptibility to
infection during use of a prevention strategy?
Mapping Program
Objective: Map mucosal function and responses in the context
of HIV -1 prevention.
Funding Mechanism
DAIDS Awards/
Projected Awards
6 of 9 DAIDS Awards to New Investigators
* NICHD: Prevention of HIV Transmission/Acquisition
through a better understanding of Reproductive
Health
Integration of the Mapping Program into the
Non-vaccine Biomedical Prevention Program
Prevention of HIV Transmission/Acquisition through a better
understanding of Reproductive Health (DAIDS Funded)
• CHIC II:Effect of COCs, DMPA, LNG-IUD and Cu-IUD on immune cell
activation and the microbiome in the cervicovagina and endometrium
in U.S. Women.
Companion study in Zimbabwe (Zim CHIC) funded by Bill and
Melinda Gates Foundation
• Exploration of the cellular and hormonal factors controlling the
susceptibility to HIV infection during the menstrual cycle.
“Window of Vulnerability” hypothesis posits that HIV susceptibility
is controlled by endogenous hormone expression in the female
reproductive tract (FRT).
• Relationship of medroxyprogesterone, levonorgestestrel and
ectonorgestrel serum/tissue concentrations to HIV target cell
numbers, phenotype and innate immune factor expression in ecto-,
endocervical and rectosigmoid mucosa. (ex vivo studies)
Prevention of HIV Transmission/Acquisition through a better
understanding of Reproductive Health (DAIDS Funded) Cont.
• Impact of DMPA on TDF/FTC concentrations in vaginal and cervical
tissues. Targets drug transporters and nucleotide phosphorylation
and metabolism in CD4+T cells.
• Longitudinal study of the impact of Depo-Provera on cervicovaginal
and colonic microbiomes and the systemic and mucosal immune
system.
Uses ex vivo determinations of HIV susceptibility.
• Hypothesizes that the type of progestin and its local concentration
are important in determining the susceptibility of the tissue to HIV
infection. Compares the effect of the DMPA and LNG (IUD) on a
number of immune and cellular markers, including transport of HIV
in mucus and in vitro anti-HIV activity of secretions.
Mucosal Environment and HIV Prevention (MEHP)
• Uses additional analysis of Partners in PrEP samples to correlate DMPA use, BV
presence and HIV infection (+/- PrEP).
• Characterize the relationship between immune activation and the FRT biome
(viral, fungal, archeal and bacterial communities, weekly for 2 years) in highrisk women in sub-Saharan Africa in the FRESH trial.
Quantitates systemic progesterone, estradiol, and medroxyprogesterone
acetate (~20% Women on DMPA) in plasma and cervicovaginal secretions
(LC-MS).
• Assessment of the endocervical inflammatory effects of Intrauterine devices
(Cu-IUD, Mirena, LNG-IUD vs. oral LNG users). Focused on determining HC
effects on immune cell activation and pro-inflammatory programmed cell
death (Pyroptosis) of HIV target cells.
Other Activities of interest
• Reengineering the Cu-IUD to delivery an ARV
• Interaction of hormonal contraceptives and Tenofovir (TFV), and
Tenofovir Alafenamide (TAF) in HIV target cells in the upper and lower
female reproductive tract (FRT).
In vivo and ex vivo effect of hormones on drug metabolizing enzymes
(NRTI activating and degrading), and innate immune
signaling/mediator expression
• Virus/cervical mucous interactions.
Discussion Questions:
HC and HIV Risk

Is the link between specific HC-receptor binding and
induction of inflammation adequately understood to assess
HIV risk?

Are the receptor binding profiles between different HC
options adequately characterized and understood?

Is there evidence of specific HC suppression or activation
of the adaptive or innate immune systems?

What is known about the effects of hormones on immune
cell trafficking in the FRT?

Are “normal” endogenous hormone (P, E, LH, FSH) levels
adequately understood to serve as markers for HIV
infection vulnerability?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Discussion Questions:
HC Dose

Can animal models be used to define topical or
systemic HC dose levels for contraceptive efficacy
in an MPT?

Is a single topical dose of HC viable to
accommodate any BMI?
– Will BMI variability likely dictate the need for MPT with
multiple HC doses?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Discussion Questions:
Topical Effects & DDI
Topical Effects:
 What is the relevance of systemic vs local FRT tissue
levels of HC on mechanism of action and
contraceptive efficacy
DDI
 HC and cellular uptake, activation, egress of ARVs?
– HC and induction/suppression of cellular transporters?
– HC induction of nucleotide pools and metabolism?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Discussion Questions:
General Considerations/Risks

Can pairing ARVs with HC in an MPT negatively
effect end user perception of the product for
contraception?

What are the major risks associated with MPT
implementation/delivery from the FP perspective?

What are the major biological issues/risks with the
combination of HC with ARV?

Are there specific HC options that currently make
more sense than others for an MPT?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Concluding Question
“Adding an ARV for HIV prevention to an established
contraceptive method will boost uptake and sustained
use of an HIV prevention intervention”
Is this hypothesis sufficiently reasonable to justify MPT
development investment?


If yes, what are the priority issues to be addressed first?
If not, what unknowns must be addressed to achieve
justification?
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Bridging the silos between
contraception & HIV prevention
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Acknowledgments




Bill & Melinda Gates Foundation
Mary Wohlford Foundation
NIH NICHD
USAID
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
The Initiative for Multipurpose
Prevention Technologies
Round Table on HC in MPTs
20 May 2015 – Rockville, MD
Thank You!
Support for this project is made possible by the generous support of the American people through the United
States Agency for International Development (USAID) under the terms of the HealthTech Cooperative
Agreement #AID-OAA-A-11-00051, managed by PATH. The contents are the responsibility of CAMI/PHI and its
partners and do not necessarily reflect the views of USAID or the US Government.
Round Table on HC in MPTs
20 May 2015 – Rockville, MD