Transcript Hormonal Contraception: Special Considerations for HIV-infected Women Lori E. Kamemoto, MD, MPH Hawaii AIDS Clinical Research Program University of Hawaii School of Medicine.

Hormonal Contraception:
Special Considerations for
HIV-infected Women
Lori E. Kamemoto, MD, MPH
Hawaii AIDS Clinical Research Program
University of Hawaii School of Medicine
Almost half of all pregnancies in
the United States are unintended
Abortion
23%
Intended
pregnancies
Unintended
pregnancies
Intended birth
43%
Mistimed/
unwanted
birth
19%
Miscarriage
9%
Miscarriage
6%
Pregnancies, 1994
(6.3 million)
Alan Guttmacher Institute
Rates higher in:
Ages 15-24 y.o.
Unmarried women
< 200% poverty level
Black and Hispanic women
Contraceptive hormones
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Ethinyl estradiol
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EE dosage decreasing
over time 80+ g  50
g  20-30 g
Estradiol cypionate
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Lunelle
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Progestins
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Norethindrone
Norgestimate
Ethynodiol diacetate
Levonorgestrol
Desogestrel
Gestodene
Drospirenone
Medroxyprogesterone
acetate
Norelgestromin
Etonorgestrol
How does hormonal contraception
work?
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Progestins
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prevent ovulation
affect the time needed for ova to travel through the fallopian
tubes, interfering with precise timing needed for fertilization
increase the amount and thickness of mucus at the cervix,
decreasing sperm entry
decrease the ability of sperm to fertilize an egg
interfere with the implantation of a fertilized egg on the wall of
the uterus
Estrogens
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used mostly to prevent progestin only effect on
menses/tissues, however is associated with increase in
contraceptive efficacy (i.e.-”mini-pill” vs. combination pill)
may also prevent ovulation and affect the time needed for ova
to travel through the fallopian tubes, interfering with precise
timing needed for fertilization
Hormonal contraceptives
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Oral contraceptives
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Contraceptive patch (E + P)
Vaginal ring (E + P)
Injectable contraceptives
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Combination pills (E + P)
Progestin-only pills (“mini-pill”)
Emergency contraception (E + P or P)
DepoProvera (P)
Lunelle (E + P)-no longer available in U.S.
Progestin IUD
New hormonal contraception
methods FDA approved since 1995
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Emergency contraception: Preven® (1998),
Plan B® (1999)
Monthly injectable: Lunelle® (2000)
Vaginal ring: NuvaRing® (2001)
Patch: Ortho Evra® (2001)
Oral contraceptive with extended period-free
regimen: Seasonale® (2003)
Awaiting approval
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Single-rod implant: Implanon®
Male hormonal contraception
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WHO studies on testosterone (1996)
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testosterone IM q week
azoospermia 65% (1 pregnancy)
oligospermia 98% (4 pregnancies)
male method should produce azoospermia, easily
reversible
Progestins plus testosterone
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progestins + testosterone more likely to produce
azoospermia
norethistrone, DMPA, levonorgestrol, desogestrol,
etonorgestrol
investigating injectables, patch, implant
Contraceptive method use by Age
100%
Pill
80%
Implant
Injectable
60%
Other
40%
IUD
M/F Steril.
20%
None
0%
25-29
30-34
35-39
40-44
Age
Gallup survey, 1998-9
HIV and contraceptive method
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Approximately 70% of all HIV infected women are sexually active
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Irish cohort of HIV+ women
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French SEROCO study HIV+ women
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39% used contraception
50% of pregnancies were unplanned, and one third were terminated
Postpartum HIV+ vs. HIV –
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20% of sexually active using no contraception
24% became pregnant and 63% of conceptions ended in abortion
African DITRAME project HIV+ women
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Only 57% of sexually active used contraception
Tubal ligation: OR 2.9 (1.4-5.9)
BCP: OR 0.2 (0.1-0.5)
Condom use: OR 0.7 (0.4-1.3)
HIV+ vs. HIV•
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Consistent condom use: OR 2.31 (1.35-3.94)
BCP: OR 0.54 (0.3-0.98)
Hormonal contraception
Benefits
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prevent pregnancy
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including ectopic pregnancy, miscarriage, abortion
 anemia
promote cycle regularity
 ovarian cysts and ovarian cancer
 endometrial cancer
 endometriosis
 PID
 dysmenorrhea
 acne
probable  colorectal cancer,  osteopenia
Hormonal contraception
Risks
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 thromboembolic phenomena
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including DVT, pulmonary embolism, stroke
 breast cancer
 heart disease (after 35 y.o. with smoking)
 gall bladder disease, hepatoma
 bone density with DepoProvera
may be associated with hypertension
irregular bleeding
nausea, headaches, weight gain
Current lower dose pills associated with
decreased risk
Hormonal contraception and HIV
Concerns for Women
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Does hormonal contraception influence…
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HIV acquisition?
HIV disease progression?
ARV pharmacokinetics?
HIV transmission to partner?
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Do ARVs influence contraceptive hormone
pharmacokinetics?
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Which contraceptive method is best for HIV
infected women?
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efficacy
least risk vs. benefit
Acquisition of HIV infection
in hormonal contraception users
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Mombasa cohort of female sex workers
attending STD clinic
Depo Provera associated with increased
incidence of HIV-1 infection
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Adjusted Hazard Ratio 2.0 (1.3-3.1)
Oral contraceptives associated with a trend
towards increased HIV-1 infection
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Adjusted HR 2.6 (0.8-8.5)
Martin 1998
Acquisition of HIV infection
in oral contraceptive users
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Meta-analysis of 28 studies
Association between HIV-1
seroprevalence and use of oral
contraception
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All 28 studies: OR 1.19 (0.99-1.42)
21 cross-sectional studies: OR 1.21 (1.011.44)
“8 best studies”: OR 1.60 (1.05-2.44)
Wang 1999
Acquisition of HIV infection
with hormonal contraception
Possible mechanisms that may increase
susceptibility to HIV acquisition with
hormone use
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Thinning of vaginal wall with progestins
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Increased SIV acquisition with progesterone
associated with vaginal wall thinning
No evidence that vaginal wall thinning occurs in
humans
Increased cervical ectropion with
combination OCPs
Transmission of HIV infection
with hormonal contraceptives
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Increased FGT HIV-1 RNA levels may lead to
increased rates of transmission to partners
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Cervical ectopy associated with increased HIV
genital tract shedding
Oral contraceptives may be associated with
increased HIV genital tract shedding
Contraceptive methods associated with irregular or
heavier bleeding (progestin-only methods, IUD)
may be associated with increased risk of HIV
transmission to partner
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HIV disease progression
and contraceptive hormones
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Mombasa cohort; Lavreys, etal (2004)
> 1500 high risk women enrolled over 10 years
Able to estimate time of HIV-1 acquisition in 161
women
Depo Provera use at the time of acquisition of HIV
associated with  HIV-1 RNA at 4 months
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HIV-1 RNA higher setpoint (+0.33 log copies/cc)
No association found with OCP use
Multiple viral variants associated with Depo Provera
and OCP use (OR 2.7, P=0.003) compared with no
contraceptive use
Women with multiple variants, were more likely to
have higher viral load and lower CD4
HIV disease progression
and contraceptive hormones
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Women’s Interagency Study examined
plasma HIV-1 RNA and CD4 count on entry
and longitudinally in women on hormonal
contraceptives
No apparent association with HIV-1 RNA
levels
Small increase in CD4 count among
hormone users of doubtful clinical
significance
• Mean increase 27.6 cells/l
Cejtin 2003
HIV-associated lipodystrophy and
estrogen receptors
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Increased risk of HIV-associated
lipodystrophy in women
Estrogen receptor  (ER) is decreased in
subcutaneous adipose tissue with HIV+
lipodystrophy
PIs appear to down-regulate ER receptors
and PI withdrawal led to increase in ER
mRNA
?role of selective estrogen modulators?
Barzon 2005
How contraceptive hormones may
affect HIV-1 disease
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Physiologic effects on the vaginal epithelium
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Hormonal effects on cell-surface CCR5 levels
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CCR5 is the main coreceptor in FGT
CCR5 increased in biopsies from “progesterone dominant” women
In vitro studies with progesterone showed increased CCR5 and
CXCR4 expression
Direct hormonal effect on virus expression
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Progesterone implants increased risk of SIV acquisition due to
thinning of vaginal epithelium
Subsequent human studies have not confirmed thinning of the
vaginal epithelium with Depo Provera
Female hormones may govern uterine immune cell synthesis of
cytokines, thus imfluencing the density and action of macrophages
More studies needed to investigate the role of hormonal
contraception on HIV-1 acquisition, viral setpoint, and viral
diversity in chronic HIV-1 infection
Marx 1996, Patterson 1998, Hunt 1998
Drug interactions
ARVs and contraceptive hormones
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Ethinyl estradiol (EE) and progestins (P) are
substrates of cytochrome P450 CYP 3A4 system of
enzymes
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Liver, small intestine
ARVS may:
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induce cytochromes, which increase the hepatic
metabolism of contraceptive hormones
inhibit cytochromes, causing decreased clearance and
increased levels of contraceptive hormones
when both interacting drugs are substrates, the interaction
is less predictable
some ARVs exhibit several of these properties
Drug interactions
ARVs and contraceptive hormones
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Most of data from pharmaceutical
contraceptive industry research involving
contraceptive hormone levels after single
dose ARV
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No information on longer term contraceptive
hormone and ARV use
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“use with caution” with certain ARVs
recent completion of ACTG 5093
No data on hormonal contraceptive efficacy
with ARVs
Oral contraceptive failure in
HIV infected women
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2035 HIV+ women in New Orleans
Retrosepctive review of 86 of these women
who were on OCPs
11 women appeared to have become
pregnant while on Depo Provera or OCPs
“OCP failure”
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PIs: 25%
NNRTIs: 10%
No PI or NNRTI: 0%
Clarke 2004
Drug interactions
ARVs and contraceptive hormones
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Associated with increase in oral contraceptive
EE levels
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EFV (EE AUC  37%)
ATZ (EE AUC  48%, NET AUC  110%)
IDV (EE AUC  24%, NET AUC  26%)
Associated with decrease in oral contraceptive
EE levels
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NVP (EE AUC  29%, NET  18%)
APV (NET  18%)
RTV (EE AUC  41%)
NFV (EE AUC  47%, NET AUC  18%)
LPV/r (EE AUC  42%, NET AUC  16%)
Drug interactions
ARVs and contraceptive hormones
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NRTIs and oral contraceptives
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Majority of NRTIs undergo renal excretion of 5085%
ABC metabolized via unique pathway and excreted
renally
ZDV undergoes glucoronidation to metabolite that is
excreted renally
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ACTG 317 demonstrated no significant difference in
glucoronidation of ZDV with OCPs
Oral contraceptive effect on ARVs
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Minimal data exists
Amprenavir AUC  22% (do not use with OCPs)
Likely minimal effect on ARVs, but little data exists
ACTG 5093, An Open-label, Non-randomized Study
of the Effect of Depo-Medroxyprogesterone
Acetate (DMPA) on the PK of Selected PI and
NNRTI Therapies Among HIV-infected Women
Primary Objective:
• Determine the effect of DMPA on the PK of selected ARV
therapies among HIV-infected women comparing the AUC’s
for these drugs prior to DMPA and 4 weeks later
Secondary Objectives:
• Determine whether PK interactions between selected ARV’s
and DMPA affect the suppression of ovulation.
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Evaluate other PK parameters including Cmax and Tmax of
selected ARVs before and after DMPA.
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Evaluate the toxicity and safety of any PK interactions
between ARVs and DMPA.
ACTG 5093, An Open-label, Non-randomized Study
of the Effect of Depo-Medroxyprogesterone
Acetate (DMPA) on the PK of Selected PI and
NNRTI Therapies Among HIV-infected Women
Enrollment and
Subjects Eligible for Analysis
NRTIs only
or No Meds
(control arm)
NFV
plus NRTIs
EFV
plus NRTIs
IDV
plus NRTIs
NVP
plus NRTIs
16
22
18
1*
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20
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ARV PK done before and 4 weeks after DMPA
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ACTG 5093, An Open-label, Non-randomized Study
of the Effect of Depo-Medroxyprogesterone
Acetate (DMPA) on the PK of Selected PI and
NNRTI Therapies Among HIV-infected Women
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Efficacy of DMPA does not appear to be altered in
the presence of NFV, EFV, and NVP-based regimens.
DMPA was well-tolerated and side effects were
similar to those reported in HIV-negative women on
DMPA Progesterone levels remained low
(<1.5ng/mL) following DMPA administration, with no
presumptive evidence of ovulation through week 12
Although NVP AUC levels were higher with DMPA,
the increased levels do not appear to be clinically
relevant
DMPA appears to be safe and effective for HIVinfected women taking NFV, EFV, and NVP-based
regimens
Studies with other HIV protease inhibitors, NNRTIs
and NRTIs (tenofovir) deserve consideration
ACTG 5188, A Phase II Pharmacokinetic Study of
the Transdermal Contraceptive System and Oral
Contraceptive in HIV-1 Infected Women on
Lopinavir/Ritonavir
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Protease inhibitors associated
with a significant decrease in oral
contraceptive (OC) estradiol
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LPV associated with 42%  OC
estradiol levels
Primary Objective: To evaluate
the effect of LPV/r on the PK of
EE by comparing the EE AUC
during ORTHO EVRA®
transdermal contraceptive patch
week 3 in women on LPV/r with
the EE AUC measured in women
who are not receiving PIs,
NNRTIs, or any ARV therapy.
 Hypothesis: Transdermal
contraceptive patch system (TCS)
estradiol levels will not be
significantly affected by PIs
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
HIV-1 infected women of
reproductive age
Arm A: LPV/r containing
regimen
 Arm B: NRTI-only regimen
or No ARVs
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
6 week PK study (OC &
TCS)
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EE
Norelgestromin
LPV
54 subjects
Open to enrollment
Hormonal contraception and HIV
Concerns for Women
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Does hormonal contraception influence…
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HIV acquisition? MAYBE
HIV disease progression? MAYBE
ARV pharmacokinetics? PROBABLY NOT for most
ARVs, altho’ minimal data available
HIV transmission to partner? MAYBE
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Do ARVs influence contraceptive hormone
pharmacokinetics? YES
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Which contraceptive method is best for HIV
infected women?
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efficacy
least risk vs. benefit
*Association of Reproductive Health Professionals