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Clinical research in women's reproductive health and the human immunodeficiency virus

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Clinical research in women's reproductive health and the human immunodeficiency virus

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CLINICAL RESEARCH IN WOMEN’S REPRODUCTIVE HEALTH AND THE
HUMAN IMMUNODEFICIENCY VIRUS

by

Jessica Maria Atrio

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS, EPIDEMIOLOGY)

August 2013
Copyright 2013 Jessica Maria Atrio

ii
Acknowledgements
The academic and clinical communities at the University of Southern California and the
Los Angeles County Hospital have been extremely supportive and intellectually
challenging. I am grateful for all my mentors, colleagues and collaborators. Laura Sech,
Daniel Mishell, Stanley Azen, Frank Stanczyk, Blanca Ovalle, Alice Stek, Sue Ingles,
Stan Louie, Michael Neely, Eva Operskalski, Neisha Opper, Wendy Mack, Loraine
O’Neil and Penina Segall-Gutierrez are a few of the persons who have contributed
tremendously to my scope of work, research, education and this document. My family
and partner are also responsible for this achievement through their unwavering support
and encouragement.
Financial conflicts of interest: none to declare
Funding Sources:
a
Society of Family Planning,
a
Southern California Clinical and
Translational Science Institute(NIH/NCRR/NCATS) through Grant UL1TR000130,
b
NIH grants GM068968 and HD070886

iii
Glossary of terms
ABC abacavir
AE adverse event
AIDS acquired immunodeficiency syndrome
ARV antiretroviral(s)
ATV atazanavir
AUC area under the concentration-time curve
CDC Centers for Disease Control and Prevention
COC combined oral contraceptive(s): containing both ethinyl
estradiol & progestin
Cmin minimum concentration
Cmax maximum concentration
CYP cytochrome
CTSI Clinical Transnational Science Institute of USC
DMPA depo-medroxyprogesterone acetate
EE ethinyl estradiol
FDA Food and Drug Administration
HAART highly active antiretroviral therapy
HIV human immunodeficiency virus
HE hormonal contraception
I interacting drug
ICH International Conference on Harmonization

iv
IRB/RSRB Institutional Review Board/Research Subjects Review
Board
IUD Intrauterine devise
LMP last menstrual period
NET norethindrone
NIH National Institute of Health
NRTI nucleoside reverse transcriptase inhibitor
NNRTI non-nucleoside reverse transcriptase inhibitor(s)
MTCT mother to child HIV transmission
P-gy P-glycoproteins MDR1
PI protease inhibitor(s) or principle investigator
PK pharmacokinetic(s)
POP oral progestin only contraceptive pill
RNA ribonucleic acid
RTV ritonavir
S substrate drug of interest
SD standard deviation
SNP single nucleotide polymorphisms
Tmax maximum time
ULN upper limit of normal
WHO World Health Organization

v
Table of Contents
Acknowledgements i
Glossary of Terms ii
List of Tables ix
Abstract xi
Chapter 1.0: Reproductive needs of HIV+ women 1
1.1 Background
1.2 Contraception in HIV+ women
1.3 Clinical indication for and metabolic properties of POP
1.4 Metabolic properties of RTV
1.5 FDA guidance on drug-drug interaction studies in vivo
1.6 Current POP recommendations in HIV+ women on ARV
1.7 Role for saving samples for interval genetic testing
1.8 Potential effect of net on cellular immunity and regulation
1.9 Previous similar studies
1.10 Hypothesis
Chapter 2.0 Objectives and purpose 10
2.1 Primary objective
2.2 Secondary objectives
2.3 Study design
2.4 Enrollment of subjects
2.4.1 Inclusion criteria and eligible ARV regimens

vi
2.4.2 Exclusion criteria and prohibited medications
2.4.3 Enrollment procedures
2.4.4 Withdrawal
Chapter 3.0 Study treatment 23
3.1 Study product formulation and preparation
3.2 Regimens and duration
3.3 Administration
3.4 Pharmacy
3.5 Study product accountability
3.6 Concomitant medications 15
3.7 CLINICAL AND LABORATORY EVALUATIONS
3.7.1 Procedures for enrolled volunteers
3.7.2 Day 0, In-depth screening visit
3.7.3 Day 0, Enrollment visit
3.7.4 Adherence 15
3.7.5 Day 1-21, Study substrate and monitoring during enrollment period
3.7.6 Day 22, PK admission
3.7.7 Day 23 & 24, Lab visits and exiting
Chapter 4 Materials and Methods 31
Chapter 5 Results 35
Chapter 6 Discussion 37
Chapter 7 Conclusion 40

vii
Figure 1: Screening, enrollment and study completion 41
Figure 2: Violin Plot of Norethindrone Area under the Curve by Group 42
Table 1: Demographic Characteristics 43
Table 2: Antiretroviral Regimens 44
Table 3: Total Cervical Mucus Score before and after 21 days of exposure to
Norethindrone 0.35 mg 45
Comprehensive Bibliography 46
Appendix: WHO cervical mucus quality score 54

viii
List of Figures & Tables
Figure 1: Screening, enrollment and study completion
Figure 2: Violin Plot of Norethindrone Area under the Curve by Group
Table 1: Demographic Characteristics
Table 2: Antiretroviral Regimens
Table 3: Total Cervical Mucus Score before and after 21 days of exposure to
Norethindrone 0.35 mg

ix
Abstract
Objective:
Pharmacokinetic interactions exist between combined oral contraceptives and protease
inhibitors (PI). However, such information is lacking for progestin-only oral
contraception. We sought to define the steady-state pharmacokinetic interaction between
norethindrone (NET) and PI in HIV infected women.
Methods and design:
I conducted an open-label, prospective, non-randomized trial to characterize the steady-
state pharmacokinetics of serum NET in HIVinfected women receiving PI compared to a
control group of HIVinfected women receiving other types of antiretroviral therapy that
does not alter NET levels. Following 21 days of NET 0.35 mg ingestion once daily,
serial serum samples were obtained at 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours. The area
under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal
approximation.
Results:
Thirty-five women were enrolled, two withdrew. Sixteen women in the PI group and 17
controls completed the study. NET half life, and maximum concentration were not
significantly different between the two groups. Minimum concentration of NET was
significantly higher in the PI group (p=0.01). The ratio of the geometric mean NET area
under the curve in the PI group compared to controls was 1.5 (90% confidence interval
1.21-1.86). NET serum concentrations are significantly higher in HIVinfected women
taking a PI compared to controls (p=0.004).

x
Conclusions:
Co-administration of PI inhibits NET metabolism as shown by higher serum NET area
under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This
study supports increased utilization of progestin only pills in HIV infected women
receiving PI.

1
1.1 Background
The HIV epidemic is one of the most significant health crises of the century. In 2009
approximately 1.2 million people in the U.S. were living with HIV, 310,000 of these
persons were women.(1, 2) Internationally the scope of the problem is more decimating,
as HIV/AIDS is the leading cause of maternal mortality among reproductive age women
(2). Current antiretroviral (ARV) therapies are comprised of 2 or more medications from
the various classes including: entry inhibitors, integrase inhibitors, CCR5 agonists,
protease inhibitors (PI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and
nucleotide reverse transcriptase inhibitors (NRTI).
About 150 million women use hormonal contraceptives worldwide. Hormonal
contraceptive use is high in many areas of the world with high HIV prevalence and their
utilization is increasing. The World Health Organization's (WHO) Medical Eligibility
Criteria for Contraceptive Use states that women at risk of HIV infection or those who
are HIV-infected on ARV therapy may use hormonal contraceptives (3). Effective
contraception and reduction in unplanned pregnancies are crucial for the prevention of
mother to child HIV transmission (MTCT). The importance of family planning services
in HIV care has begun to gain more recognition among local and international health
organizations. The prevention of unintended pregnancy, so as to improve maternal health
and combat HIV, have been incorporated into the strategic plan promoted by the United
Nation’s Millennium Development Goals for 2010-2015 (4).

2
1.2 Contraception in HIV+ women
It is recognized that there is a dearth of clinically applied, population based, empiric data
to guide contraceptive recommendations in HIV + women on ARVs (5). PI and NNRTI
induce micro enzyme systems such as CYP 3A4, which in turn alters the bio-availability
and pharmacokinetics of other concurrently administered medicaitons.(6) Empiric trials
from small samples, often of 5-10 HIV negative subjects, have demonstrated that
concurrent administration of combined oral contraceptives (COC) and a PI or a NNRTI
have been associated with decreased plasma ethinyl estradiol (EE) levels (7-15). These
pharmacokinetic findings have raised concern that decreased bio-availability of EE may
result in decreased contraceptive efficacy, with possible increased unintended pregnancy.
Some of these COC studies have demonstrated that there is no change in the serum levels
of norethindrone (NET) on ARVs (3, 16, 17). However, there is no published data
focused on oral NET or oral progestin-only pills (POP) to inform management in HIV+
women (17).
1.3 Clinical indication for and metabolic properties of oral progestin-only
contraceptive pills (POP)
POP have fewer contraindications than estrogen containing methods, allowing greater use.
For example: women with hypertension, history of venous thrombosis, smokers greater
than 35 years of age, and women in the postpartum period can all take POP and would be
discouraged from using EE containing COC. NET 0.35 mg daily is administered as a
continuous oral contraceptive dispensed in U.S. manufactured POP. The half-life of NET
is 8-12 hours, peak plasma concentration occurs within 1-2 hours. Up to 75% of NET is

3
bound to albumin and far less is bound to sex hormone binding globulin. Mean area
under the NET plasma concentration vs. time curve with 0.3 mg NET was noted to have a
mean of 22.1 ng/ml and a standard deviation of 10.9 (18, 19). In vitro studies have
demonstrated that hydroxylation of NET to its M1 metabolite is predominately due to
oxidative and hydrolytic CYP 3A4 catalyzed reactions in the hepatic endoplasmic
reticulum and to a lesser degree in the small intestine (19, 20). CYP2C19 enzymes may
have a minor role (20). Oral contraceptives are a substrate of CYP3A4 however, they
are not considered to be sensitive substrates (21). Additionally, CYP3A4 is subject to
wide degree of inter-subject enzymatic variability, in the order of 11-20 fold, but it has
not demonstrated the genetic polymorphisms seen in other CYP isoforms, such as 2D6,
2C9, 2C19 (19).
1.4 Metabolic properties of RTV
CYP3A inhibitors are classified as strong, moderate or weak based on their in vivo fold
change in plasma area under the curve (AUC) for known enzyme substrates (such as oral
midazolam). A strong inhibitor results in a 5 fold increase in AUC, a moderate inhibitor
alters AUC by 2 to 5 orders of magnitude, and a weak inhibitor is associated with a 1.25
to 2 fold increase in plasma AUC (21). Ritonavir (RTV) is a strong inhibitor of P-
glycoproteins MDR1 (P-gy) and OCT-1 transporters in the liver and other sites. P-gy
transporters are members of the ATP-binding cassette transporters, expressed by ABCB1
genes, and are present on the apical side of epithelial cells in a range of tissues (small
intestine, proximal tubule, hepatocytes).

4
RTV, atazanavir (ATV), indinavir (IDV), nelfinavir, and saquinavir are all strong
inhibitors of CYP3A4 micro enzyme systems (21). RTV acts via rapid, reversible,
competitive binding (21). It is used synergistically with other PI to increase plasma drug
concentrations and enhance ARV patient response. RTV is the preferred PI in
conjunction with ATV or darunavir (TMC114) in ARV naïve patients (6). RTV 100mg
is orally administered and taken once daily. The minimum trough concentration of ATV
should be >150ng/mL (6). PI also inhibit UDP-glucuronosyl transferase, with decreased
P-GY transport and excretion activity (21). Based on these in vitro observations it would
be expected that plasma steroid levels would be increased following co-administration of
COC and PI. However, in vitro models do not always correlate with in vivo drug
interactions (19, 21). Changes in distribution, absorption, and excretion may be altered
by direct drug interactions, in addition to hepatic-metabolism based changes (21).
Several studies to date have demonstrated decreased as well as increased serum PK
results with co-administration of COC and ARV.
1.5 FDA guidance on drug-drug interaction studies in vivo
As per the Food and Drug Administration (FDA) Guidance for Industry Drug Interaction
Studies the substrate drug (S) is the drug of interest, namely NET, and the interacting
drug (I) is suspected to result in a change in serum availability, namely RTV: “Results of
drug-drug interaction studies should be reported as 90% confidence intervals about the
geometric mean ratio of the observed pharmacokinetic measures with (S+I) and without
the interacting drug (S alone). Confidence intervals provide an estimate of the
distribution of the observed systemic exposure measure ration of (S+I) versus (S alone)

5
and convey a probability of the magnitude of the interaction. In contrast, test of
significance are not appropriate because small, consistent systemic exposure differences
can be statistically significant (P< 0.05) but not clinically relevant”(21). Additionally,
there is a range of systemic pharmacokinetic exposures and parameters that are
considered to be clinically equivalent. This range is defined as a “no effect boundary”
and may be defined by 90% confidence interval surrounding population averages.
Alternately when data regarding population averages are not available the no effect
boundary can be approximated as 80-125% of the observed expected systemic exposure
(21). These considerations were utilized in the design, analysis and reporting of results
for this trial.
1.6 Current POP recommendations in HIV+ women on ARV
Multiple studies have demonstrated the safety and efficacy of depo-medroxyprogesterone
acetate (DMPA), another progestin only contraceptive, in HIV+ women and women on
ARV (22-24). However, there is no data to support the contraceptive efficacy and
clinical safety of POP in HIV+ women on ARV. Manufacturer materials advise patients
to utilize alternative methods of contraception when taking both ARV and COC or POP
(6, 10). This is due to data that indicated decreased serum levels of EE in women taking
ARV and COC, without any outcome data related to ovulation, change in cervical mucus
or increased pregnancy incidence.
The World Health Organization (WHO) and Center for Disease Control (CDC) base their
POP contraception recommendations on studies of concurrent COC and ARV
administration (3, 25). POP are category 2 in conjunction with NNRTI and category 3

6
with RTV boosted PI. As noted in the CDC Appendix M “small mostly unpublished
studies suggest that some ARV therapies might alter the PK of COC”(25). In the absence
of data surrounding POP in HIV+ women on ARV, POP are categorized with the same
risks and precautions as COC. Progestin only contraceptive methods require less
restrictive screening, have wider distribution potential, and can increase access to
contraception among medically complicated women (26). POP are an underutilized, safe
and effective contraceptive option in HIV+ women.
POP is a cost effective contraceptive option with an advantageous safety profile. Wider
distribution and prescription of these methods in resource poor settings could impact
unplanned pregnancies, maternal mortality, and MTCT. A significant barrier to the
administration of these medications is the absence of empiric data describing POP in
HIV+ women taking ARV regiments. The cytochrome enzymes that induce EE
metabolism many not be implicated to the same degree or result in the same magnitude of
drug-to-drug interactions that affected NET with PI and other ARV. There is a distinct
possibility that the progestin steroid bioavailability and serum levels many not be affected
to a clinically significant degree by the co-administration of PI. If this is the case
evidence from our study will support the role for increased utilization of POP in HIV+
women on ARV. Which in turn will reduce barriers to the utilization of this safe and
effective contraceptive method in a high-risk population that has one of the most
compelling international needs for the prevention of unplanned pregnancy.

7
1.7 Role for saving samples for interval genetic testing
This trial represented a unique opportunity to collect serum specimens from HIV+
women taking various ARV therapies with POP. Metabolic differences may be the result
of genetic polymorphism, such as CYP2D6 genotypes, or other identifiable confounders
such as age, race or gender (21). Research to date has not identified any steroid gene
alleles or single nucleotide polymorphisms (SNPs) that may result in altered NET
metabolism. Published trials have demonstrated that the metabolism of NNRTI efavirenz
and nevirapine have been affected by the CYP P450 2B6 516 allele polymorphism (27,
28). Drug interaction studies may be enhanced by incorporating the opportunity and a
provision to subsequently evaluate the phenotype and or genotype of volunteers for
polymorphisms, especially CYP2D6, CYP2C19 and CYP2C9 which have been
demonstrated to impact drug metabolism (21). We plan to store research labeled, de-
identified serum samples from all consenting subjects. Genetic testing may be performed
to look for variants that may account for outliers or unexpected profiles.
1.8 Potential effect of NET on cellular immunity and regulation
There is evidence that the use of hormonal contraceptives may increase the risk of HIV
acquisition and accelerate progression of HIV infection in women who are not on ARV
therapy. Pregnancy, a state of heightened female hormone production, has also been
associated with a modest increase in the risk of HIV acquisition in sex workers (29).
Compared with HIV-infected women using non-hormonal birth control methods, HIV-
infected women on COC had higher HIV RNA concentrations in genital secretions (30).
The results of these studies may be influenced by socioeconomic and behavioral

8
characteristics of the study population that are difficult to separate from those directly
generated by the use of COC on the risk of HIV acquisition or progression. However,
studies in animal models of SIV or HSV acquisition found an increased risk of infection
in animals treated with supra-theraputic, supra-physiologic doses of female hormones
(31, 32). These models suggest that the immuno-modulatory consequences of high
steroid hormone exposure may have clinical consequences (related to virus acquisition or
disease progression) that warrant further study.
Weinberg and others have investigated the ex vivo effect of estrogen and progestins with
varicella zoster models on cell-mediated Th1 immunity and pro-inflammatory cytokine
secretion (25, 33, 34). There is a significant increase in CD4+, IL10+, and Tregs during
the luteal phase compared with the early and late follicular phases. The Treg increase
significantly correlates with the increase in progesterone levels during luteal phase. We
plan to store vaginal lavage samples for future analysis of cytokines and inflammatory
markers that will inform how POP may interact with cellular immunity.
1.9 Previous similar studies
There are no published trials focused on POP or specifically on oral NET without the co-
administration of EE in HIV+ women on ARV. The U.S. Department of Health, NIH,
WHO, CDC, as well as other HIV focused health organizations publish and regularly
revise their recommendations regarding ARV therapy and contraceptives, with a focus on
drug interactions (6, 35).
Several pharmacokinetic trials have been conducted in HIV positive and negative
subjects looking at the concurrent administration of PI, EE, and NET as dosed in COC.

9
The following interactions have been noted with PI. The magnitude of increase or
decrease from controls ranges from 14% to 110%:
Decreased EE has been demonstrated with atazanavir/ritonavir, darunavir/ritonavir,
fosamprenavir/ritonavir, nelfinavir, lopinavir/ritonavir, and saquinavir/ritonavir
(6,7,11,12,15,23,36, 37, 38, 39). Increased EE and NET with atazanavir, and
fosamprenavir.(6) No change in NET with idinavir, or nelfinavir (11,14). Decreased
NET with darunavir/ritonavir, fosamprenavir/ritonavir, tipranavir/ritonavir,
lopinavir/ritonavir (6, 7, 12, 39).
Trials have been conducted in HIV positive and negative subjects to examine the
concurrent administration of NNRTI, EE, and NET as dosed in COCs. The following
interactions have been noted and the magnitude of increase or decrease ranges from a
14% to 83% deviation from controls:
No change in NET with etravirine, rilpivirine (6, 40). No change in EE with efavirenz (8,
13, 23). Increased EE with etravirine, rilpivirine (6, 40). Decreased EE and NET with
nevaripine (41, 42). Trials related to the concurrent administration of COC and NRTIs
have revealed no changes in EE, NET, zidovudine or tenofovir (43,44).
1.10 Hypothesis
RTV will alter the norethindrone serum area under the curve (AUC) in HIV+ volunteers
due to inhibition or induction of the CYP 3A4 enzyme and P-gy transporter by the ARV.
This two arm, open-label, prospective, steady state pharmacokinetic (PK) study of drug-
drug interactions in HIV infected women treated with norethindrone (NET), the substrate,
while receiving daily PI therapy, the interacting drug.

10
Chapter 2.0 Objectives and purpose
2.1 Primary objective and endpoint
To detect a ±40% difference in AUC of serum NET in HIV+ women taking PI as
compared to AUC of NET in HIV negative and HIV + women taking an ARV regimen
that has demonstrated no interaction with NET in the past. HIV negative control women
will not be given ritonavir or any other antiviral medications.
Primary endpoint: Natural log-transformed NET PK parameter AUC from 0 to 72 hours
following oral administration, with multiple discrete serum data points for each subject
on PI. This will be compared to natural log-transformed NET PK AUC from 0 to 72
hours following oral administration, with multiple discrete serum data points for controls
HIV+ women taking an ARV regimen that has demonstrated no significant interaction
with oral NET in the past.
2.2.1 Secondary objectives
The sample and control groups mentioned above will again be compared to evaluate the
effect of PI on other PK exposure endpoints and parameters of NET: minimum plasma
concentration (Cmin), maximum plasma concentration (Cmax), time to Cmax (Tmax),
and half-life (T
1/2
).
2.2.2 To score and evaluate cervical mucus quality at enrollment (day 0) prior to NET
administration and after 21 days of NET administration.

Mucus assessment is a surrogate
marker of efficacy. Women were enrolled and had a baseline cervical mucus score prior
to NET administration. Mucus collection was repeated after 21 days of daily NET on
days 22 to 24. Mucus scoring was assessed for: volume, consistency, cellularity,

11
spinnbarkeit, and ferning, according to the World Health Organization criteria.
2.3 Study design & rationale
This will be a two arm open-label, prospective, steady state pharmacokinetic (PK) study
of drug-drug interactions in HIV infected women treated with norethindrone (NET), the
substrate, while receiving daily PI therapy, the interacting drug. The first primary
objective is to evaluate the effect of the PI on the pharmacokinetics of NET in HIV-
infected women. These volunteers will be compared to a control group of HIV negative
and HIV infected women treated with norethindrone (NET) while taking an ARV
regimen that has demonstrated no significant interaction with NET in the past. HIV
negative control women will not be given PI.
The subjects are not randomized to the treatment arms due to the following reasons: (1)
All subjects are required to be on stable ARV regimens for a minimum of 21 days prior
to enrollment to assure steady state (2) The lack of a well defined available study
population of treatment-naïve women required for randomization to ARV regimens and
NET would severely impair study accrual, may be medically compromising to HIV+
women’s well being, and is not practical to implement. There must be no intention of
modifying the ARV regimen or women changing any of their medications throughout the
duration of the study. Regimens will be considered suitable and stable for the volunteer
as judged by her infectious disease practitioner, without plan for modifications during the
study period. The team does not anticipate any change in immunologic status during the
brief study enrollment period. ARV therapy will not be provided by this study and
volunteers will demonstrate that they have a means of continuing their current medication

12
regimens. A 21-day course of NET 0.35 mg daily will be initiated on day 1 following
enrollment (day 0). Following completion of the trial volunteers will be given the option
to continue NET outside of the protocol, if they have not experienced adverse events
(AE).
Following review of inclusion and exclusion criteria, confirmation of a negative
pregnancy test, and documentation of informed consent volunteers will contribute
baseline blood samples at the time of enrollment.
Also, at the time of enrollment and after 21 days of NET cervical mucus will be sampled
and scored using WHO grading criteria (Appendix A). Additional serial blood samples
will be draw for PK analysis of NET, as well as other secondary outcomes, after 21 days
of NET exposure.
2.4 ENROLLMENT OF SUBJECTS
2.4 Inclusion criteria and eligible ARV regimens
2.4.1 Women will not be taking any ARV medications. Alternately, a woman taking an
ARV regimen will be considered suitable and stable for the volunteer as judged by her
infectious disease practitioner, without plan for modifications during the study period.
She must be on this regimen for at least 21 days prior to enrollment. Volunteers eligible
for enrollment in the study arm will be taking PI with the possible addition of an ARV as
listed acceptable for the control arm in the following paragraphs. Acceptable control
regimens include no ARV, NRTI combinations, entry inhibitors, integrase inhibitors, and
CCR5 agonists. NRTI combinations may include but are not limited to: zidovudine

13
(ZDV), lamivudine (3TC), emtricitabine (FTC), didanosine (ddl), stavudine (d4T),
abacavir (ABC), and tenofovir disoproxil fumarate (TDF).
Patient utilizing the following NNRTI will be eligible due to published trials
demonstrating no interaction with NET when administered as dosed in COC: etravirine,
and rilpivirine. Patients utilizing the following NNRTI will not be eligible do to
published trials demonstrating an interaction with NET when administered as dosed in
COCs: nevirapine. Concurrent dual nucleoside therapy of ZDV and d4T will be excluded.
Patients on additional NNRTI not herein listed will be evaluated on a case-by-case basis
with ongoing review of published recommendations.
A history of HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme
or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
confirmed by a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
NOTE: The term “licensed” refers to a U.S. FDA-approved kit. The World Health
Organization (WHO) and the Centers for Disease Control and Prevention (CDC)
guidelines mandate that confirmation of the initial test result must use a test that is
different from the one used for the initial assessment. A reactive initial rapid test should
be confirmed by either another type of rapid assay or an E/CIA that is based on a
different antigen preparation and/or different test principle (e.g., indirect versus
competitive), or a Western blot or a plasma HIV-1 RNA viral load.
The control group may also be comprised of women who are HIV negative. As protease
inhibitor therapy is a common component of ARV therapy there is a concern that it may

14
be challenging to identify HIV+ women who are utilizing a regiment that fits the control
profile. Based on chart review at our Maternal Child Adolescent Clinic (as subsequently
described) there should be approximately > 50 women who fit this profile. However,
recruitment was be closely scrutinized. Recruitment goals were met and no HIV negative
volunteers were required. It is common place and accepted that National level drug
interaction trials utilize HIV- women as controls. The FDA has accepted this comparison
for drug development and PK trials. HIV negative control women will not be given
ritonavir or any other antiviral medications.
A volunteers self reported HIV negative status was sufficient. Researchers offered to
assist volunteers in getting HIV testing if they would like to get this test completed.
Additionally, risk factors for recent exposure to HIV or HIV acquisition: IV drug use,
unprotected intercourse, occupational exposure, will be reviewed with the volunteer.
Referrals will be made to clinics, urgent care and volunteers’ primary care providers if
HIV testing is indicated (due to preference or risk). Enrollment will be deferred until the
participant has accessed HIV testing.
Menstrating females, 18-44 years of age, without a history of bilateral oophorectomy or
ovarian dysfunction.
Documentation of plasma CD4+ cell count ≥200 cells/mm
3
and or no current profound
immuno-compromise. Researchers may refer to last assessment by infectious disease
team or seek out consultation from the patient’s primary practitioner. These studies will
be ordered and processed as indicated by primary medical team managing each subject’s
ARV care.

15
No current liver or renal disease defined as the following lab values drawn on routine
examination or for symptomatic work up by review of medical records:
Platelet count ≥ 50,000 platelets/mm
3

International normalized ratio (INR) ≤1.8.
Aspartate transaminase (SGOT) and alanine aminotransferase (SGPT) < 5 x upper limit
of normal (ULN)
Creatinine ≤ 1.5 x ULN
Total bilirubin ≤2.0 x ULN
All subjects must agree that they have no intention of or desire to conceive (e.g., active
attempt to become pregnant or in vitro fertilization) for the duration of the study.
Subjects who are or plan to become sexual activity must agree to consistently use an
effective method of nonhormonal contraception throughout the time of enrollment, which
could include: condoms (male or female) with or without a spermicidal agent, diaphragm
or cervical cap with spermicide, non-hormonal intra-uterine devise (IUD), or sterilization.
Condoms will be provided to all volunteers.

Willingness to abstain from any grapefruit product or supplement for the duration of the
study (due to the irreversible Cyp3A4 inhibition by furanocoumarin).
BMI <40 kg/m^2
2.4.2 Exclusion criteria and prohibited medications:
2.4.1 Receipt of the following prohibited medications within 21 days prior to study entry:
amiodarone (Cordarone®),

16
astemizole (Hismanal®),
bepridil (Vascor®),
buspirone (BuSpar®),
carbamazepine (Tegretol®),
cisapride (Propulsid®),
clarithromycin (Biaxin®),
cyclosporine (Sandimmune®, Neoral®),
dihydroergotamine (Migranal® and others),
diltiazem (Cardiazem®)
ergotamine (Ergostat®, Gotamine®, and others),
erythromycin (E-mycin®, EES® and others),
flecainide (Tambocor®),
glucocorticoids,
Hypericum perforatum (St. John’s wort),
itraconazole (Sporanox®),
ketoconazole (Nizoral®),
lovastatin (Mevacor®),
midazolam (Versed®),
nefazadone (Serzone®),
nevirapine,
nifedipine (Procardia®),

17
phenobarbital (Luminal®),
phenytoin (Dilantin®),
pimozide (Orap®),
pioglitazone (Actos®),
pravastatin
propafenone (Rythmol®),
propofol (Diprivan®),
quinidine (Quinidex®),
rifabutin (Mycobutin®),
rifampin (Rifadin, Rifamate®, Rifater®, Rimactane®),
rosiglitazone (Avandia®),
simvastatin (Zocor®),
tacrolimus (Prograf®),
terfenadine,
ticlopidine (Ticlid®),
triazolam (Halcion®),
verapamil
zidovudine and didehydrodeoxythymidine (ZDV and d4T)
2.4.2 CYP 3A4 substrates: Subject cannot have initiated, stopped, or changed doses of
the medications below, which are CYP 3A4 substrates, within 21 days before study entry.
The subject can remain on stable doses of the following medications during the study:

18
benzodiazepines, except midazolam (Versed®) and triazolam (Halcion®) are prohibited.
Allowable benzodiazepines include, but are not limited to: alprazolam (Xanax®),
clozapine (Clozaril®), diazepam (Valium®), estazolam (ProSom®), flurazepam
(Dalmane®), oxazepam (Serax®), temazepam (Restoril®), etc. Volunteers should be on
stable regiments of bupropion (wellbutrin®, Zyban®), and calcium channel blockers,
except diltiazem (Cardiazem®), verapamil, and nifedipine (Procardia®), which are
prohibited. Volunteers should be on stable regiments of fluconazole (Diflucan®),
isoniazid (INH), mexiletine (Mexitil®), zaleplon (Sonata®), and zolpidem (Ambien®).
Stable regimens of HMG CoA reductase inhibitors, such as: atorvastatin (Lipitor®),
cerivastatin (Baycol®), fluvastatin (Lescol®) are acceptable. However, pravastatin,
lovastatin (Mevacor®), and simvastatin (Zocor®) are prohibited.
Contraindications to POP as indicated by the CDC Medical Eligibility Criteria (25),
hypersensitivity or allergy to NET or any of the ingredients in the POP preparation.
Current pregnancy, breastfeeding or pregnancy within 30 days of enrollment.
Depomedroxyprogesterone acetate injection (DMPA) within 180 days prior to study
entry.
Other hormonal therapies (e.g. oral contraceptive agents, Provera, vaginal ring,
contraceptive patch, monthly contraceptive injection, hormone replacement therapy,
anabolic therapies, including nandrolone decanoate or megestrol acetate) within the 21
days prior to study entry.
More than a 50% change in tobacco smoking within the 14 days prior to study entry or

19
plans to significantly change tobacco use during the study.
Currently on methadone maintenance treatment for less than 60 days prior to study entry.
Volunteers will not be allowed to eat any food or drink any beverage containing alcohol,
apple or orange juice, vegetables from the mustard green family (kale, broccoli,
watercress, collard greens, kohlrabi, Brussels sprouts, mustard) or charbroiled meats for
48 hours prior to and during the PK admission. No significant changes in dietary
practices should take place during the course of the enrollment.
Subjects unable to adhere to the medications regimens or study protocol, in the opinion of
the study team.
Active drug or alcohol use or dependence that, in the opinion of the investigator, would
interfere with adherence to study requirements.
Invasive cancer of the reproductive tract, undiagnosed vaginal bleeding, or liver tumors.
Uncontrolled thyroid disease. Volunteer must be on stable thyroid medication as assess
by primary practitioner or infectious disease team.
2.4.3 Enrollment procedures:
Once a potential candidate for study entry has been identified and demonstrated interest,
an initial telephone or in-person screening visit will be obtained to review inclusion
criteria. If she remains eligible she will be scheduled for an in-depth screening and
enrollment visit. Details of the study requirements will be carefully discussed with the
subject. Volunteers will be counseled regarding the risks and benefits of enrollment in
their language of choice, all questions will be answered and they will be provided with a

20
copy of the written consent form. The subject will be asked to read and sign the
approved protocol consent form.
Subjects will be recruited from the USC Maternal, Child and Adolescent Center for
Infectious Diseases and Virology, USC family planning clinic, USC prenatal clinics and
greater LA community, by study investigators and coordinators, as well as clinic staff.
Flyers will be posted in clinical environments and waiting rooms of LAC USC and USC
affiliated facilities. Subjects may be recruited from other clinics, media postings or
public information forums however; they will be required to bring medical records and
materials for review by research team to determine eligibility. Coordinator contact
information will posted on all materials and offered to all interested volunteers.
2.4.4 Withdrawal criteria & discontinuation events
All subjects who are withdrawn will have the opportunity to meet with the research team
and discuss their status with the study coordinators or investigators. They will be offered
appropriate contraception and/or referral for general care in Los Angeles County hospital
system. All volunteers will remain patients at the Maternal, Child and Adolescent
Center for Infectious Diseases and Virology, University of Southern California Keck
School of Medicine or their respective subsequent clinic. Volunteers have access to care
irrespective of enrollment in this study or of its outcomes. A log of all screened, enrolled
and withdrawal volunteers will be maintained with their research data. Other volunteers
will be screened to replace withdrawn subjects and additional participants will be accrued.
This may result in the need to screen and enroll volunteers above the number required by
the protocol sample size calculations.

21
Women who are enrolled but are unable to subsequently follow up with the research as
prescribed by the protocol or are unable to adhere to their medication regiments including
the study substrate (NET) will be counseled in depth by the investigator and coordinators.
If an appropriate plan to ensure adherence to the protocol is not identified these subjects
will be removed.
Volunteers who miss NET pills will be counseled in depth by the investigator and
coordinators. If an appropriate plan to ensure adherence to protocol is not identified
these subjects will be removed.
All medication changes will require careful evaluation as indicated in by current drug-
drug interaction publications and manufacturer information. Following a change in
medication a participant may not be eligible for PK admission and may be subject to
study discontinuation. Additionally refer to 4.2 regarding prohibited medications.

2.4.4 A participant may not be eligible for PK admission and may be subject to study
discontinuation if any of these conditions are encountered: she misses any of her
prescription medications with attention to her ARV and NET regimens within 48 hours
prior to PK sampling. She is unable to complete all recommended serum collections
during the course of the PK admission.
Subject will be withdrawn if the study team or her primary physicians decide that
continued participation in the study would be harmful to the subject’s health or well
being.

22
Women who become pregnant will be referred for options counseling and prenatal care in
addition to any other indicated referrals and support. They will be removed from the
study.

23
Chapter 3.0 Study treatment
3.1 Study product formulation and preparation
Study drug is norethindrone (NET). It is a progestin with 19-nor-17α-ethynyltestosterone
structure. The half-life of NET is approximately 8-12 hours. Up to 75% of NET is
bound to albumin and far less is bound to sex hormone binding globulin. This
formulation is FDA approved for contraception and is commercially available. It is
manufactured as a progestin only birth control pill (POP) in a 0.35 mg daily formulation
to be taken continuously. The following pharmaceutical companies manufacture NET
POP in 28-day blister packs:
Ortho-McNeil, Micronor
Watson, Nor-QD, Jolivette, and Nora-be
Barr, Camilla & Errin
ARV therapy is required as indicated by a volunteer’s primary physician and infectious
disease team however, it is not provided by this study.
3.2 Regimens and Duration
At study entry/ Day 0, subjects will receive a 28-day blister pack of the study drug NET.
Prior to administration of NET, subjects will undergo serum sampling of ARV levels.
Volunteers will be required to continue their current ARV therapy and will have a
demonstrated means to obtaining their prescribed medications. All other indicated
medications will not be provided through the study. Volunteers will complete a
minimum of 21 days of continuous daily NET administration prior to 12 hours of PK
serum collection of NET. Daily NET will be continued until women can be scheduled

24
for admission and serum sample collection. Study subjects must be on a stable ARV
regimen as indicated in the inclusion, exclusion and withdrawal criteria. For subjects
requiring changes in ARV therapy during the study, they will likely require withdrawal.
3.3 Administration
Patients will be instructed on daily administration of NET at 8 am each day. The
importance of adherence to strict dosing time, dietary and exposure regiments and
restrictions will be discussed in depth with the patient. All ARV therapy as well as any
other prescribed medications will be taken at the same time each day. Volunteers will be
required to avoid herbal supplements, certain foods and drinks as well as any changes in
alcohol or smoking habits for the duration of the enrollment, as well as 14 days prior to
enrollment. In the event that women request and overnight PK admission there will be
consideration for regular administration of the study substrate at a designated evening
time such as 7pm.
3.4 Pharmacy: Product Supply, Distribution, and Accountability
NET will be available through the USC pharmacy. The site pharmacist will obtain the
study product from the manufacturer and follow guidelines regarding storage, dispensing
and handling of the drug according to the manufacturer guidelines.
3.5 Study Treatment: NET 0.35 mg (Jolivette), manufactured by Watson
Pharmaceuticals, Inc., was ordered, stocked and monitored by the USC research
pharmacy. All volunteers received prescriptions and medication was dispensed at
enrollment.

25
3.6 Concomitant Medications
To avoid adverse events caused by drug interactions, researchers must refer to the most
recent package inserts for study drugs and concomitant agents whenever a volunteer is
utilizing a medication prior to enrollment or will be continuing a medication during the
course of enrollment. All volunteers will be enrolled with the stipulation that there is no
intention of changing their current medication regimen. If a new medication is initiated
or a dose is changed, investigators will review the concomitant medications and study
agents. A review of drug-drug interactions as published by the manufacturer and as per
National guidelines will be reviewed. This process will be clearly documented. Subjects
that are prescribed medications with known drug-drug interactions that directly impact
serum NET will be counseled and withdrawn from the study. A list of prohibited
medications, is in the exclusion criteria 4.2
3.7 CLINICAL EXAMINATIONS AND LABORATORY EVALUATIONS
3.7.1 Procedures for enrolled volunteers:
3.7.2 Day 0, In-depth screening visit: In-depth screening will consist of informed
consent and documentation as mentioned above in the enrollment section of this protocol,
provision of screening ID number, and pregnancy test. If the screening examination and
tests as indicated by the inclusion or exclusion criteria are considered adequate, she will
be enrolled in the study and given a study ID number.
3.7.3 Day 0, enrollment visit: This visit will likely occur on the same day of the in-
depth, in person screening visit. Investigators and coordinators will record the relevant
information mentioned above. Other data will include: demographic information, date of

26
birth, gravidity, parity, birth weight, medical and surgical history, gynecologic and
menstrual history, allergies, medication history with stop and start dates (as indicated in
the table below), substance use, social history, and prior contraceptive use. Vital signs
will be collected including temperature, height, weight, pulse, respiration rate, and blood
pressure. A complete physical examination is performed and includes: the examination
of the skin, head, mouth, neck, auscultation of the lungs, cardiac exam, abdominal exam,
examination of the lower extremities, gynecological exam, cervical mucus evaluation,
and collection of baseline serum labs. The principal and co-investigators will collect
cervical mucus according the standard practices outlined by the WHO scoring criteria
(Appendix A). Cervical mucus will be grossly and microscopically examined for volume,
consistency, cellularity, spinnbarkeit, and ferning, as detailed by WHO Criteria for
Cervical Mucus Evaluation in the WHO Laboratory Manual (45). Blood will be
collected for archival samples.
Study drug will be dispensed by the pharmacy. Study materials including medication
diary, investigator and participant contract, and a subject specific schedule of events and
appointments will be discussed and distributed. Each subject will be compensated $40
for the screening visit and $40 for each visit thereafter.
3.7.4 Adherence will be carefully discussed at enrollment Day 0. Participants will be
encouraged to maintain perfect adherence, and they will be made aware that they cannot
miss any doses in the 48 hours prior to the PK labs. Adherence counseling and
assessments will be periodically completed by telephone. In addition, ARV and NET
adherence assessment using the study provided self-report questionnaire will be utilized.

27
A side effect and medication diary will be distributed to participants at enrollment. This
medication diary will be reviewed and collected at the PK admission.
3.7.5 Day 1-21, Study substrate and monitoring during enrollment period:
Volunteers will take the study drug and all other prescribed medications at regular
intervals. Investigators and coordinators will periodically contact participants to aid with
adherence to the study regimen and visits. Additionally, subjects will be instructed to call
the coordinators or PI to report side effects, AE, new prescription medications or
diagnoses, vaginal bleeding or spotting, a missed pill, or if they have any questions. A
volunteer will have the opportunity to schedule an appointment with the investigators or
coordinators throughout the course of enrollment. Any indicated treatments,
examinations, or referrals will be facilitated and advocated on a case-by-case basis.
All women will also be instructed at the start of the study regarding what to do if they
miss a pill. If one pill is missed, the subject will take it as soon as she remembers and
call the researchers. If two pills are missed, a subject should take both pills as soon as
she can and then resume taking 1 pill a day thereafter. Again she should contact the
researchers. She will not be eligible for PK studies and will be offered withdrawal or the
opportunity to reattempt daily NET for three continuous weeks followed by the PK visit
for serial lab collection.
3.7.6 Day 22, PK admission:
Women will be scheduled for admission for serum PK collection after 21 days of
continuous NET. Women will utilize PK collection areas and observation facilities in the
CTSI. If women are unable to present on day 22 they will have the option of presenting

28
for admission on day 23-27. They will be required to continue all medications as
prescribed by the protocol. During the PK admission samples will be collected prior to
final NET ingestion and at 1, 2, 3, 4, 6, 8, and 12 hours following observed ingestion of
NET. Plasma ARV levels, and albumin will be collected. During this PK admission,
vaginal lavage, and cervical mucus scoring will be completed by PI or investigators.
ARV adherence questionnaire and medication diary will be collected. Women will be
compensated $180 for the PK admission.
So as to accommodate working women or women with inflexible daytime commitments
we will collaborate with the CTSI so as to schedule an overnight PK sampling. At
enrollment participant that report a day time admission to the CTSI would be prohibitive
will be considered for an overnight admission. With prior collaboration with the CTSI to
determine scheduling women will be instructed to take NET in the evening and will
present for the PK admission at 6pm. They will then have the subsequent lab collections
performed in the evening according to the same interval spacing.
In consideration of the fact that several of the recruited volunteers seek all their health
care services at the Maternal, Child and Adolescent Center for Infectious Diseases &
Virology LAC+USC (MCA) and also utilize the childcare services at the MCA clinic
researchers will explore potentially executing PK serum collections at MCA clinic.
Effort will be made to primarily schedule all PK collections at the CTSI. However, the
CTSI is able to accommodate at 13 hour PK collection on Thursday and Friday.
Additionally, clinic patients have expressed apprehension presenting to any other LAC
USC or local care facility. There is a strong therapeutic alliance with women and their

29
clinical providers at MCA. Some volunteers may not be willing to present to an outside
clinical setting for research (such as the CTSI) and the CTSI may not be able to schedule
their PK admission (due to their availability). Multiple PK trials have been complete at
the MCA facilities. They have a designated clinical space with television, comfortable
accommodations, child care services, catering and support staff. The research team will
investigate the potential for identifying competent research staff and a schedule that
would allow for women to have their PK admission at the MCA.
3.7.7 Day 23, 24, & 25 lab visits and exiting:
Additional plasma NET collections will be completed at 24, 48 and 72 hours following
ingestion of NET, according to the same schedule assigned during the PK admission. If
the PK admission occurred on day 23-27 of enrollment due to scheduling constraints then
these subsequent labs will be collected accordingly to preserve the previously mentioned
time intervals. This duration corresponds with 5-8 half lives of NET, which is
approximately 8-12 hours. Women will be compensated $40 for each lab visit. Exiting
phone interviews will assure that patients have follow up with the Maternal, Child and
Adolescent Center for Infectious Diseases and Virology Clinic or their designated
physician for continued primary and HIV related health needs. Subjects will be
counseled regarding availability of contraceptive services and referrals will be offered.
Blood collection for 3 days following PK admission at LAC USC clinical facilities or the
participants’ residence or mutually agreed upon location. Members of the MCA clinic
routinely visit patient homes for research serum collections, wound checks, and
adherence guidance. Members of the MCA research team identified that it may enhance

30
adherence and the ability for all lab samples to be collected following the PK admission
if members of the research team are able to collect samples at a location convenient to the
participant, such as her home. This was especially considered on days such as Saturday
and Sunday.

31
Chapter 4.0 Materials and methods
Study design: This was a two arm, open-label, prospective, non-randomized, steady state
pharmacokinetic trial of drug-drug interactions in HIV infected women treated with oral
NET and PI. Area under the time concentration curve of these women was compared to
HIV infected controls taking no antiretroviral or an antiretroviral regimen without a PI,
that have demonstrated no significant interaction with NET in previous combined oral
contraceptive trials. University of Southern California Institutional Review Board
approval was obtained.
Study population: Participants were HIV infected, 18 to 44 years of age, had no major
lifestyle changes or changes in medications in the month prior to enrollment, no recent
exposure to hormonal contraceptives (combined oral contraceptives > 30 days, depot
medoxyprogesterone acetate > 180 days), no evidence of immunocompromise, CD4 cell
count ≥200 cells/mm
3
, no liver or renal disease, normal ovulatory function, body mass
index <40 kg/m
2
, > 30 days post partum, abstained from grapefruit products (which
contain furanocomarin) or other CYP3A4 interacting substances, and agreed to use non-
hormonal contraception. Women who were taking any PI as part of their anti-HIV
therapy formed the study group, and women who were not taking a PI served as controls.
Women were recruited from the Maternal Child Adolescent Clinic of Los Angeles
County, University of Southern California.
Study Procedures: Following screening and informed consent, women received a 28-
day blister pack of NET (Jolivette, NET 0.35 mg, from Watson Pharmaceuticals, Inc.)
from the USC research pharmacy. Women took a single daily fixed dose of 0.35 mg

32
NET for a minimum of 21 days, and also adhered to dietary restrictions as per the
protocol. On or after day 22 each woman was admitted to the Clinical Trials Unit at the
University of Southern California, where a clinician observed her final ingestion of NET.
Blood was collected by venous catheter and venipuncture prior to NET ingestion, and at
1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after taking NET. After allowing the blood to
stand for approximately 1 hour, the samples were centrifuged, serum was removed and
stored at -20°C until analyzed.
Assays: Norethindrone (NET) was measured in serum by radioimmunoassay (46, 47).
Prior to radioimmunoassay, NET was extracted with ethyl acetate:hexane (3:2) and then
purified by Celite column partition chromatography. It was eluted off the column in 20%
ethyl acetate in isooctane. Procedural losses were followed by adding small amounts of
high specific activity tritiated internal standard (
3
H-norethindrone) to the serum prior to
the extraction step. A highly specific antiserum was used in conjunction with an
iodinated radioligand in the radioimmunoassay. Separation of unbound from antiserum-
bound NET was achieved by use of second antibody. The sensitivity of the NET
radioimmunoassay was 0.06 ng/ml. Intraassay and interassay coefficients of variation
(CVs) range from 4-7% and 9-12%, respectively.

Study
Endpoints:
The
primary
study
endpoint
was
the
serum
NET
area
under
the

time
concentration
curve
from
0-‐72
hours,
calculated
using
the
linear
trapezoidal

approximation.
Secondary
endpoints
were
maximum
NET
concentration,
minimum

NET
concentration
and
the
half-‐life,
which
was
estimated
from
the
terminal

33
elimination
slope
for
each
patient
using
concentrations
sampled
at
12
hours
and

beyond.

For
area
under
the
curve
and
half-‐life,
we
used
the
Pmetrics
package
for
R

(48).

Secondary
endpoint
of
cervical
mucus
was
conducted
in
a
resarcher
blinded

fashion.

Mucus assessment is a surrogate marker of efficacy. Women were enrolled and
had a baseline cervical mucus score prior to NET administration. Mucus collection was
repeated after 21 days of daily NET on days 22 to 24. Mucus scoring was assessed for:
volume, consistency, cellularity, spinnbarkeit, and ferning, according to the World Health
Organization criteria.
Statistics and Sample Size: The null hypothesis used was that the 90% confidence
interval for area under the curve

geometric mean ratio would be within the range of 0.6 to
1.67, which is a clinically insignificant difference of ≤40% (21). To reject the null
hypothesis, we estimated that 16 women would be required in each arm to detect a >40%
inter-group difference in area under the curve with a two-tailed alpha of 0.05 and 80%
power. Our assumptions for the sample size calculation were based on a previously
reported mean (standard deviation) NET area under the curve of 22.1 (10.9) ng×hr/ml

after an oral dose of NET 0.3 mg (18).

We summarized normally distributed, continuous data with means and standard
deviations, and compared groups with Student’s t-test. We summarized non-normally
distributed, continuous data, we summarized them with medians and interquartile ranges,
and compared them with the Wilcoxon rank sum test. Categorical data were compared
with Fisher’s exact test and displayed as numbers and percentiles. Log 10 transformation

34
was completed for all pharmacokinetic endpoints. We used SAS (version 9.3) and R
(version 3.0.0) for all analyses and plots.

35
Chapter 5: Results
Of 167 women who were screened, 132 were ineligible based on protocol restrictions or
because they declined to participate, as shown in Figure 1. One of 17 women in the study
group withdrew due to commitments that conflicted with her scheduled admission. One
of 18 enrolled in the control group withdrew due to medication change. Therefore, 16
women in the study group and 17 in the control group completed the trial. There were no
significant differences between the two groups in terms of mean age, parity, CD4, history
of opportunistic infections, body mass index, smoking status, ethnicity or language, as
shown in Table 1. In the control group four women were not taking any antiretroviral
therapy. Other control participants were taking combinations of nucleoside reverse
transcriptase inhibitors (N=14), non-nucleoside reverse transcriptase inhibitors (N=9),
and integrase inhibitors. Fifteen in the study group took ritonavir, and 11 took atazanvir
(Table 2). The majority of women were taking a combination of antiretroviral
medications.
The pharmacokinetic characteristics of NET in the study and control groups are shown in
Table 2. The geometric mean NET area under the curve in the PI study group was 37.8
ng x hr/ml

and in the control group it was 25.2 ng x hr/ml

(Figure 3). The geometric
mean area under the curve ratio of the PI study group to the controls was 1.50, with a
90% confidence interval of 1.21 to 1.86 (P=0.004). NET minimum concentration was
higher among women taking a PI; while maximum concentration was not significantly
different between the study groups (P=0.11), it tended to be higher in the PI group. The
half-life was similar between the groups.

36

Baseline cervical mucus examination was similar in both groups (p=0.28, Table 3).
HIV + women taking daily oral NET contraception in the PI study group and women in
the control group without PI therapy had similar cervical mucus scores after 21 days
(p=0.1). Both groups demonstrated thickened cervical mucus

37
Chapter 6 Discussion
It is recognized that there is a dearth of clinical data to guide contraceptive
recommendations in HIV infected women taking antiretroviral therapy (5). The WHO
and CDC base their progestin only pill recommendations on studies of antiretroviral
drugs and combined oral contraceptives (25). Progestin only pills are Category 3 with
ritonavir-boosted PI. As noted in the CDC Appendix M “small mostly unpublished
studies suggest that some antiretroviral therapies might alter the pharmacokinetics of
combined oral contraceptives” (25). Progestin only pills have fewer contraindications
than estrogen-containing products, allowing greater use by more women. For example,
women with hypertension, a history of venous thrombosis, smokers greater than 35 years
of age, and women in the postpartum period may all take progestin only pills and would
be discouraged from using ethinyl estradiol containing combined oral contraceptives.
Furthermore, many HIV positive women have co-morbidities that would prevent them
from using combined oral contraceptives. Additionally, they have a compelling need for
dual contraception with condoms and an alternative method.

Strengths of this trial included blinding, no inter-examiner variation and the prospective
design. A limitation was that baseline assessment did not involve peri-ovulatory cervical
mucus assessment. Enrollment period was limited and the research team did not have the
ability to maintain enrollment through a confirmed follicular cycle of ovulation. This
trail contributes to the existing literature that demonstrates the efficacy in offering HIV+
women on PI therapy POPs. The cervical mucus scoring was not statistically different

38
among women taking a PI therapy as compared to women taking ARV without PI or no
ARV.
This present study showed area under the curve of NET is significantly increased, by
50% among HIV infected women taking PI therapy as compared to controls. This ratio
met our predefined criteria for a significant interaction, and we rejected the null
hypothesis of no interaction. Because many PI, particularly ritonavir, are known to be
inhibitors of CYP3A4 (10), and NET is a substrate for CYP3A4 (45), we presume that
the mechanism of the interaction relates to the activity of this enzyme. In vivo the
CYP3A4 inhibition typical of PI resulted in significantly increased serum NET levels, by
decreasing systemic metabolism; this finding is supported by the increased area under the
curve and increased minimum concentration of NET. The NET half-life is not
significantly different between the two groups, which may be due to changes in steroid
distribution. It is interesting that administration of combined oral contraceptives and PI
have resulted in decreased serum ethinyl estradiol visa vi micro enzymes alterations
(references). As per the product New Drug Application label ritonavir is known to be an
inducer, as well as an inhibitor of CYP3A4, and drug-to-drug interactions are difficult to
predict (45).

The 50% increase in the area of NET noted among women taking PI in our study is not
concerning for toxicity and does not warrant dose reduction. Many progestins are well
tolerated, exhibit minimal side effects and have excellent safety profiles (53). The safety
of this steroid and its metabolites has been demonstrated in clinical trials as well as post-

39
market surveillance (53). Several of the current combined oral contraceptive products
approved and marketed in the U.S. contain 1.5 mg of NET in addition to EE; which is
over 4 times as much progestin as the 0.35 mg of NET in the progestin only pill (50-53).
The dose determined for progestin only pills contraception was a somewhat arbitrary
historic assignment based on suspected bioequivalence of chlormadinone acetate 0.5 mg
(54-58). In preliminary trials with the progestin NET, it was given in doses up to 20 mg,
which demonstrates the wide therapeutic index, safety and minimal toxicity of NET (53).

40
Chapter 7 Conclusions
Compared to combined oral contraceptives, progestin-only pills require less restrictive
screening, have wider distribution potential, and can provide an additional safe
contraception option for women with HIV. This is the first trial to describe NET
progestin-only pill pharmacokinetics in HIV infected women taking PI. NET area under
the curve is increased by co-administration of PI and cervical mucus is thickened and
consistent with contraceptive effect. Increased serum NET levels are a surrogate marker
of continued therapeutic contraceptive efficacy. This research supports increased use of
progestin only pills in HIV infected women taking PI. These findings should alter
current progestin only pill medical eligibility recommendations for women taking
protease inhibitors.

41
Figure 1: Screening, enrollment and study completion

42
Figure 2. Violin Plot of Norethindrone Area under the Curve by Group*

*The width of violin area corresponds to the mass of the data. A traditional box and
whisker plot is centered within each violin, where the filled circle is the median, the
lower and upper bounds of the box are the 25
th
and 75
th
percentiles (i.e. the interquartile
range [IQR]), the dashed “whiskers” indicate the range of the data within 1.5 IQR of the
box boundaries, and the open circle is an outlier outside this range. Exclusion of this
outlier did not change the results significantly (data not shown).

43
Table 1: Demographic Characteristics
Study* Control* P value
Age (IQR)** 39.9 (35.9-42.3) 38 (33.4-41.3) 0.6
Nulliparous ^ 3 (9.1) 0 (0) 0.1
Parity (IQR)** 3 (1-4) 3 (2-4) 0.3
CD4 cells/mm
3
(IQR)**
618.5 (398-883.5) 669 (479-749) 0.65
OI (%)*** 5 (31.3) 4 (23.5) 0.71
BMI (IQR)**** 26.8 (25.5-33.8) 29 (24.1-32.8) 0.9
Smoker^ 3 (18.8) 2 (11.8) 0.66
Ethnicity & race^
White 11 (69) 12 (71) 1.0
Black 4 (25) 4 (24)
Asian 1 (6) 1 (6)
Primary language^
English 7 (44) 6 (36) 0.73
Spanish 9 (56) 11 (65)
Total 16 17
^ Number (%)
*Study group took protease inhibitor (PI) therapy, control group took no PI protease
inhibitor
**Median at enrollment (Interquartile range)
***Opportunistic infections diagnosed in the past
****Body mass index = kg / m
2

44
Table 2: Antiretroviral Regimens^

Study*
(n 16)
Control* (n
17)
Total
PI*
Atazanavir/ritonavir^^ 11 0 11
Darunavir/ritonavir 3 0 3
Lopinavir/ritonavir 2 0 2
NNRTI**
Etravirine 1 2 3
Rilpivirine 0 7 7
NRTI***
Tenofovir 0 7 7
Emtricitabine 0 7 7
Integrase inhibitors
Raltegravir 3 4 7
No HIV therapy 0 4 4
^Several participants took multiple medications
^^One participant was taking ATV monotherapy
* Study group took protease inhibitor (PI) therapy, control group took no PI
** NNRTI nonnuceloside reverse transcriptase inhibitor
*** NRTI nucleoside reverse transcriptase inhibitor

45
Table 3: Total Cervical Mucus Score before and after 21 days of exposure to
Norethindrone 0.35 mg*
PI** Control** P value***
Categorical
Baseline
≥9 4 (25) 8 (47)
<9 12 (75) 9 (53) 0.28
Follow up****
≥9 1 (6) 1 (6)
<9 15 (94) 16 (94) 1
Continuous
Baseline
Median (IQR) 6 (2.5-8.5) 5 (3-11) 0.28
Follow up****
Median (IQR) 3.5 (2-6) 4 (2-6) 1
Total 16 17 33
*Outlined by World Health Organization scoring criteria, comprised of volume,
consistency, cellularity, spinnbarkeit, and ferning. Total ≥9 indicative of cervical mucus
favoring sperm penetration
** Study group took protease inhibitor (PI) therapy, control group took no PI
***Wilcoxon rank sum test
***After 21 days of norethindrone ingestion daily

46
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54
Appendix: WHO Cervical Mucus Quality Score
SCORE 0 1 2 3
Volume 0mL .1mL .2mL .3+mL
Consistency Thick, highly
viscous
Intermediate
viscosity
Mildly
viscous
Normal
mid-cycle
pre-
ovulatory
mucus
Ferning No
crystallization
Atypical
ferning
Primary and
secondary
stem ferning
Tertiary and
quaternary
stem ferning
Spinnbarkeit <1cm 1-4cm 5-8cm ≥9cm
Cellularity ≥11cells/HPF 6-
20cells/HPF
1-
5cells/HPF
0 cells/HPF
Scoring: ≥ 9 indicative of good cervical mucus favoring sperm penetration

Abstract (if available)

Abstract Objective: Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV infected women. ❧ Methods and design: I conducted an open-label, prospective, non-randomized trial to characterize the steady-state pharmacokinetics of serum NET in HIV infected women receiving PI compared to a control group of HIV infected women receiving other types of antiretroviral therapy that does not alter NET levels. Following 21 days of NET 0.35 mg ingestion once daily, serial serum samples were obtained at 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation. ❧ Results: Thirty-five women were enrolled, two withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half life, and maximum concentration were not significantly different between the two groups. Minimum concentration of NET was significantly higher in the PI group (p=0.01). The ratio of the geometric mean NET area under the curve in the PI group compared to controls was 1.5 (90% confidence interval 1.21-1.86). NET serum concentrations are significantly higher in HIV infected women taking a PI compared to controls (p=0.004). ❧ Conclusions: Co-administration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports increased utilization of progestin only pills in HIV infected women receiving PI.

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Creator Atrio, Jessica Maria (author)

Core Title Clinical research in women's reproductive health and the human immunodeficiency virus

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 07/16/2015

Defense Date 07/16/2013

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag antiretroviral,contraception,contraceptive,drug interaction,HIV,hormonal contraception,norethindrone,Norvir,OAI-PMH Harvest,pharmacokinetics,pregnancy prevention,progestin only pills,protease inhibitor

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Advisor Mishell, Daniel (committee chair), Azen, Stanley P. (committee member), Stanczyk, Frank (committee member)

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