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Effects of protease inhibitor use on combined oral contraceptive pharmacokinetics and pharmacodynamics in HIV-positive women

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Effects of protease inhibitor use on combined oral contraceptive pharmacokinetics and pharmacodynamics in HIV-positive women

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Content
Effects of Protease Inhibitor Use on Combined Oral Contraceptive Pharmacokinetics
and Pharmacodynamics in HIV-positive Women

Teresa Barcellos, MD
Clinical, Biomedical, and Translational Investigations
Master of Science
University of Southern California
August 9, 2016

2
Table of Contents

Background Page 3

Methods Page 4

Results Page 5

Discussion Page 8

References Page 9

3
Background
HIV currently occurs in approximately 16 million women worldwide
1
,
including an estimated 280,000 women in the United States
2
. Effective
contraception is a key component of the care of women infected with HIV, both for
optimization of maternal health and prevention of perinatal transmission
1,2
.
However, data to guide contraceptive use among HIV-positive women remains
markedly limited. In particular, while the World Health Organization (WHO)
Medical Eligibility Criteria for Contraceptive Use (MEC)
3
state that women with HIV
and women on anti-retroviral therapy are eligible to use hormonal contraception,
concerns remain regarding the efficacy of combined oral contraceptives (COCs) in
the large number of women using antiretroviral (ARV) regimens containing the
protease inhibitor ritonavir.
Currently, the Center for Disease Control (CDC) MEC rates COCs category 3
for women on ritonavir-boosted regimens due to concerns about decreased COC
efficacy resulting from interactions with the cytochrome p450 3A4 (CYP3A4)
hepatic enzyme system
4
. Protease inhibitors, including ritonavir, are considered
strong inhibitors of the CYP3A4 system
5
. As contraceptive steroids are also
metabolized by the CYP3A4 system, ritonavir would be expected to increase ethinyl
estradiol (EE) and progestin levels in women taking COCs. Surprisingly,
pharmacokinetic studies of COC users have paradoxically demonstrated decreased
levels of EE in women taking protease inhibitors
6-16
, including ritonavir
8-12
.
Conversely, the same studies have shown great variation in the effects of
protease inhibitors on the progestin components of COCs
6-17
, ranging from a 18%
decrease in norethindrone area-under-the-curve (AUC)
14
to a 110% increase in AUC
of norethindrone
15
. Moreover, few studies have attempted to correlate observed
pharmacokinetic effects of protease inhibitors with pharmacodynamic effects,
particularly ovulation, in women taking COCs. Those that did evaluate ovulation
used only a single serum progesterone level, most often drawn on day 21 of a cycle
of COC use
5,6,15
. Since ovulation during a pill cycle occurs unpredictably, this may
have overlooked ovulation occurring earlier in the cycle. Furthermore, two of these
three studies evaluated the effects of protease inhibitors used in the treatment of
Hepatitis C, which may not be generalizable to ritonavir
6,7
.
In addition, the majority of existing studies of pill use in conjunction with
protease inhibitors have used norethindrone-containing COCs
6-8,,11,15,17
. Although
levonorgestrel (LNG)-containing COCs are among the most commonly-prescribed
COCs in the United States
18
, only one small study investigated the pharmacokinetics
of a pill containing norgestrel
16
, with conclusions limited by small sample size. As a
result, better understanding the potential efficacy of specifically LNG-based COCs in
women on ritonavir is of particular interest.
The current study was a prospective cohort and steady-state
pharmacokinetic study. Our primary aim was to compare the pharmacokinetics of
LNG in women on ritonavir-boosted protease inhibitors to those in women on
regimens known not to interact with COCs. Secondary objectives were to compare
the pharmacokinetics of ethinyl estradiol and the prevalence of ovulation, defined as
any serum progesterone greater than 3ng/dL, in the two groups.

4
Methods
Study Design
This was a prospective cohort and steady state pharmacokinetic study of
interactions between protease inhibitors and LNG and EE. The study population was
composed of two groups of HIV-positive women, (1), those taking antiretroviral
regimens that include ritonavir-boosted protease inhibitors (exposed) and (2)
women on regimens previously shown not to affect COC metabolism or on no
antiretroviral medication (unexposed). Eligible medications included entry
inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, and
CCR5 agonists
19
. The study was approved by the University of Southern California
Institutional Review Board.

Study Population
Participants were HIV-positive ovulatory women aged 18-45 with no
contraindications to COC use and no anticipated medication or lifestyle changes
during the study period. Women were excluded if they had used depot
medroxyprogesterone acetate in the prior 180 days, other hormonal contraception
within 30 days, had been pregnant within 30 days, had a CD4 count less than 200
cells/mm3 or other evidence of significant immune compromise, or were unable to
comply with study procedures. Women taking efavirenz, nevirapine, or cobicistat
were excluded due to previously observed effects on CYP450 3A4.
Participants were recruited from the Los Angeles County-University of Southern
California Medical Center (LAC-USC) clinics.

Study Procedures
Potentially eligible women were invited for a screening and enrollment visit
in the mid-luteal phase of their menstrual cycle. At that visit, informed consent was
obtained and a serum progesterone level drawn. Women with progesterone levels
less than 3ng/dL were excluded due to anovulation. After confirmation of ovulation,
women began taking the LNG 150mcg/EE 30mcg (Marlissa, Glenmark Generics Inc,
Mahwah, NJ) on day 1-3 of their next menstrual cycle. The medication was
continued for 21 days, during which twice-weekly serum progesterone levels and
weekly LNG levels were obtained. On the last day of active pill use, women
presented to clinic for a 12-hour pharmacokinetic visit. LNG and EE levels were
obtained at 0, 1, 2, 3, 4, 6, 8, and 12 hours. Participants returned at 24, 48, and 72
hours for additional LNG and EE levels.

Assays
All hormone assays were conducted by the USC Reproductive Endocrine
Research Laboratory. Progesterone levels were determined by a competitive
chemiluminescent immunoassay on the Immulite analyzer (Siemens Healthcare
Diagnostics, Deerfield, IL), which has an assay sensitivity of 0.1ng/mL. Based on a
prior study
20
, women with one or fewer LNG levels of less than 1 ng/dL were
considered consistent users, while women with all levels less than 0.1 ng/dL were
considered non-users. Those with more than one level less than 1 ng/dL but some
detectable levels were considered inconsistent users. A serum progesterone level of
5
3ng/mL was considered consistent with ovulation
21
. LNG and EE levels were
determined by previously described radioimmunoassay at the University of
Southern California Reproductive Endocrine Research Laboratory.
22

Sample Size and Data Analysis
A prior study examined LNG pharmacokinetics in women taking ARV therapy
to women not on ARV medication
16
and found an increase of approximately 30% in
LNG AUC in women taking ARV compared to those not on therapy. In order to have
80% power to detect the same change in AUC with an alpha of 0.05, we needed to
recruit 10 women per group
Our primary outcome, LNG AUC from 0 to 72 hours, was calculated in
standard fashion using the linear trapezoidal rule, and compared between those
women taking ritonavir and those on regimens that do no interact with COCs. Other
standard PK parameters, including time to maximum concentration (Tmax),
maximum concentration (Cmax), and minimum concentration (Cmin) were also
calculated and will be compared between the two groups using two-sample t-tests.
EE PK parameters, including AUC, Cmax, Cmin, and Tmax will be similarly calculated
and compared between groups. Finally, any participant with a single progesterone
value of at least 3ng/mL during the study period was considered ovulatory. Planned
analysis included a comparison between the proportion of ovulatory women in each
group using Fisher’s Exact test. This report contains preliminary data from those
participants who completed the study as of June 2016 and therefore no formal
statistical analysis has been conducted.

Results
A total of 18 women were screened, of whom 3 were ineligible. The
remaining 15 women were enrolled in the study and all participants completed all
visits (Figure 1).
The current analytic cohort comprised 10 unexposed and 5 exposed women.
Levonorgestrel levels were available for 2 exposed and 7 unexposed women while
progesterone data were available for 3 exposed and 8 unexposed women. Ethinyl
estradiol levels were not yet available.
There were no meaningful differences between groups with respect to age,
BMI, parity, prior opportunistic infections, or tobacco use (Table 1). All women in
the exposed group were taking ritonavir, 3 in conjunction with atazanavir and the
remainder with darunavir. All women in the exposed group were taking
emcitracibine/tenofovir in addition to protease inhibitors. In the unexposed group,
the majority of patients were taking a combination medication comprising
emcitracibine/rilpivirine/tenofovir. Other regimens used by participants are
described in table 2.
6

Figure 1. STROBE diagram

Table 1. Characteristics of participants
Protease inhibitor Non-protease
inhibitor
Age (mean +/-SD) 36.8 +/- 4.60 35.2 +/- 3.85
Race/Ethnicity
(n/%)

Hispanic 5 (100%) 8 (80%)
African or
African-American
0 2 (20%)
BMI (mean +/- SD) 26.5 +/- 1.96 28.5 +/- 3.33
Normal 1 (20%) 1 (10%)
Overweight 4 (80%) 7 (70%)
Obese 0 2 (20%)
CD4 (mean +/-SD) 577 +/- 350 821 +/- 181
Parity (mean) 3.4 2.4
Tobacco use
(n/%)
0 1 (10%)
Screened: 18
Ineligible
-Progesterone <3: 2
-Other: 1
Enrolled: 15
Protease Inhibitor:
5
Completed study: 5
Other regimens: 10
Completed study:
10
7

Table 2. Antiretroviral regimens
Protease
Inhibitor
Non-protease
Inhibitor
PI
Atazanavir/ritonavir 3 (60%) n/a
Darunavir/ritonavir 2 (40%) n/a
Emcitracibine/Rilpivirine/
Tenofovir
0 8 (80%)
Emcitracibine/Tenofovir 4 (80%) 0
Abacavir/Dolutegravir/
Lamivudine
1 (20%) 1 (10%)
Rilpivirine 1 (20%)
None n/a 1 (10%)

One participant in the unexposed group had levonorgestrel monitoring levels
suggestive of inconsistent use (one undetectable level and one additional level
<1ng/mL). The remaining participants all had weekly LNG levels reflective of
consistent pill use.
The mean LNG AUC in the exposed group was 326 ng*hr/mL
while in the unexposed it was 235 ng*hr/mL, reflecting a 38.7% increase. The
maximum concentration was similarly higher in the exposed group (8.45 vs 6.44
ng/mL), while the time to achieve maximum concentration was slightly longer (4 vs
2 hours) (Table 3, Figure 2).
No women in either group ovulated during the course of the study.

Table 3. Pharmacokinetic Profiles
Protease Inhibitor
(N=2)
Non-protease
inhibitor (N=7)
Levonorgestrel
AUC 0-72h
(ng*hr/ml)
326 235
Cmax (ng/mL) 8.45 6.44
Cmin (ng/mL) 2.21 1.88
Tmax (hours) 4 2
8

Figure 2. Graphical presentation of LNG levels over 72 hours.

Discussion
Though contraception is an important consideration for women living with
HIV, data to guide contraceptive counseling in this population remains scant. The
current study adds information about the pharmacokinetics of a COC containing
levonorgestrel, one of the most commonly prescribed progestins,
18
in women taking
protease inhibitors. While a prior study examined the effects of other ARV regimens
on norgestrel pharmacokinetics,
16
this is the first to specifically address the effects
of ritonavir-boosted protease inhibitors on levonorgestrel pharmacokinetics.
Our preliminary data are consistent with two prior studies suggesting that
coadministration of protease inhibitors increases the AUC of the progestin
component of combined hormonal contraceptives.
9,10
Similarly, Atrio and
colleagues found an increase in norethindrone AUC among women taking ritonavir-
boosted protease inhibitors in combination with a norethindrone-containing
progestin-only contraceptive pill.
17,23
This is in contrast to Sekar and colleagues,
who found a slight but significant decrease in NET AUC when an NET-EE pill was
given with ritonavir-boosted darunavir.
11
These differences may be related to
differences in effect between specific protease inhibitors, as our initial data include
one participant each taking darunavir/ritonavir and atazanavir/ritonavir. Another
intriguing possibility is that COC metabolism differs between HIV-positive and –
negative women, as suggested by Stuart and colleague’s findings of increased LNG
AUC in HIV-positive women not on any ARV as compared to HIV-negative controls.
16

Interestingly, among those studies finding increased progestin AUC, both Vogler and
colleagues
10
and Atrio and colleagues,
17
like the current study, conducted studies of
HIV-positive women, while Zhang and colleagues
9
studied healthy volunteers.
Prior studies
7,12
have focused on changes in EE levels resulting from PI-
contraceptive interactions. Though EE results for the current study are not yet
available, we anticipate a decrease in EE similar to consistent changes observed by
others.
8-12
However, given that the contraceptive efficacy of COCs is primarily
driven by the progestin component, decreased EE would not be expected to result in
decreased contraceptive efficacy.
0
1
2
3
4
5
6
7
8
9
0 20 40 60 80
Protease Inhibitor (N=2)
Non-Protease Inhibitor
(N=7)
9
In addition, this study adds fairly rigorous assessment of ovulation to
pharmacokinetic data. We found no evidence of ovulation among study
participants, suggesting adequate ovarian suppression during pill use. Prior studies
have similarly found suppressed levels of progesterone at single time points during
pill use;
6,7,16
we were able follow progesterone levels throughout a cycle to confirm
absence of ovulation. Moreover, all participants had ovulatory midluteal
progesterone levels prior to enrollment, making it more likely that anovulation
during the study is attributable to pill use.
The current study had several limitations. The majority of participants were
Hispanic and of overweight BMI, which may not accurately reflect the demographics
of other regions. In addition, the planned total sample size, while powered for the
anticipated difference in LNG AUC, was small. Furthermore, at present data are
available for only a fraction of participants, and recruitment in the PI arm is ongoing.
Finally, the study relies on pharmacokinetic and pharmacodynamic data as
surrogate markers for pregnancy risk. Though ovarian suppression is often used as
a marker for contraceptive efficacy, COCs may also act through other mechanisms,
such as changes in cervical mucus. However, these mechanisms appear to be largely
progestin-driven and consequently are unlikely to be impaired in the setting of
increased LNG levels. Thus, while ovulation and pharmacokinetics remain imperfect
surrogates for pregnancy risk, the combination of suppression of ovulation and
increased LNG AUC suggests that COCs are likely to retain efficacy in women taking
ritonavir-boosted protease inhibitors. Results thus far support continuing
investigation of the interaction between COCs and ritonavir-boosted protease
inhibitors. If final data are consistent with the current preliminary findings, this
would support changing eligibility criteria to remove restrictions on access to COCs
in this population.

References
1. The Joint United Nations Programme on HIV/AIDS, www.unaids.org, accessed on
August 18, 2014
2. Centers for DiseaseControl, www.cdc.gov/hiv, accessed on August 18, 2014
3. WHO guidance statement
4. Centers for Disease Control and Prevention. U.S. Medical Eligibility Criteria for
Contraceptive Use, 2010. MMWR 2010 Jun 18;59(RR-4):1-86.
5. U.S. Department of Health and Human Services Food and Drug Administration.
Guidance for Industry Drug Interaction Studies- Study Design, Data Analysis, and
Implications for Dosing and Labeling. Clinical Pharmacology, Sept 2006.
6. Lin WH, Feng H-P, Shadle C, O’Reilly T, Wagner JA, Butterton JR. Pharmacokinetic
and pharmacodynamic interactions between the hepatitis C virus protease inhibitor,
boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone. Eur J Clin
Pharmacology 2014; 70(9): 1107-13.
7. Garg V, van Heeswijk R, Yang Y, Kauffman R, Smith F, Adda N. The
Pharmacokinetic Interaction Between and Oral Contraceptive Containing Ethinyl
Estradiol and Norethindrone and the HCV Protease Inhibitor Telaprevir. J Clin
Pharmacology 2012; 52: 1574-1583.
10
8. Kassera C, Li J, March B, O’Mara E. Effect of Vicriviroc With or Without Ritonavir
on Oral Contraceptive Pharmacokinetics: A Randomized, Open-Label, Parallel-
Group, Fixed-Sequence Crossover Trial in Healthy Women. Clin Therapeutics 2011;
33: 1503-1514.
9. Zhang J, Chung E, Yones C, Persson A, Mahnke L, Eley T, Xu X, Bertz R. The effect of
atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing
ethinyl estradiol and norgestimate in healthy women. Antiviral Theraphy 2011; 16:
157-164.
10. Vogler MA, Patterson K, Kamemoto L, Park J-G, Watts H, Aweeka F, Klingman KL,
Cohn SE. Contraceptive Efficacy of Oral and Transdermal Hormones When Co-
Administered With Protease Inhibitors in HIV 1-Infected Women: Pharmacokinetic
Results of ACTG Trial A5188. J Acquir Immune Defic Syndr 2010; 55(4): 473-482.
11. Sekar VJ, Lefebvre E, Guzman SS, Felicione E, De Pauw M, Vangeneugden T,
Hoetelmans RM. Pharmacokinetic interaction between ethinyl estradiol,
norethindrone and darunavir with low-dose ritonavir in healthy women. Antiviral
Therapy 2008; 13: 563-569.
12. Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, Leonard JM,
Granneman GR. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in
healthy female volunteers. Br J Clin Pharmacol 1998; 46: 111-116.
13. VICTRELIS™ (boceprivir) Capsules: US Prescribing Information 2011. Merck &
Co, Inc, Whitehouse Station, NJ.
14. Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M,
Robinson P. Pharmacokinetic Interaction Between Nevirapine and Ethinyl
Estradiol/Norethindrone When Administered Concurrently to HIV-Infected Women.
J Acquir Immune Defic Syndr 2002; 29; 471-477.
15. Reyataz (atazanavir): US Prescribing Information 2009. Bristol-Meyers Squibb,
Princeton, NJ.
16. Stuart GS, Moses A, Corbett A, Phiri G, Kumwenda W, Mkandawire N, Chintedze J,
Malunga G, Hosseinipour M, Cohen MS, Stanczyk FZ, Kashuba A. Pharmacokinetics
and Pharmacodynamics of a Combined Oral Contraceptive and a Generic Combined
Formulation Antiretroviral in Malawi. J Acquir Immune Defic Syndr 2011; 58(2):
e40-e43.
17. Atrio J, Stanczyk F, Neely M, Cherala G, Kovacs A, Mishell D. Effect of Protease
Inhibitors on Steady-State Pharmacokinietics of Oral Norethindrone Contraception
in HIV-Infected Women. J Acquir Immune Defic Syndr 2014; 65: 72-77.
18. Creinin MD. Types of Combined Oral Contraceptives Used by US Women.
Contraception 2013; 88: 192-193.
19. Tseng A, Hills-Nieminen C. Drug interactions between antiretrovirals and
hormonal contraceptives. Expert Opin Drug Metab Toxicol 2013; 9: 559–572.
20. Westhoff CL, Torgal AH, Mayeda ER, Stanczyk FZ, Lerner JP, Benn EKT, Paik M.
Ovarian Suppression in Normal-Weight and Obese Women During Oral
Contraceptive Use: A Randomized Controlled Trial. Obstetrics and Gynecology 2010;
116 (2); 275-283.
21. Israel R, Mishell DR, Stone S, Thorneycroft IH, Moyer DL. Single luteal phase
serum progesterone as an indicator of ovulation. Am Jour Obstet Gynecol 1972; 112
(8): 1043-1046.
11
22. Stanczyk FZ, Hiroi M, Goebelsmann U, Brenner PF, Lumkin ME, Mishell DR.
Radioimmunoassay of serum d-norgestrel in women following oral and intravaginal
administration. Contraception 1975; 12 (3): 279-98.
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2015; 91: 71-75.

Abstract (if available)

Abstract Background: Contraception is a key component of healthcare for HIV-positive women as it promotes maternal health and helps reduce perinatal transmission. Unfortunately, evidence to guide contraceptive choice among women living with HIV remains limited. Currently the Centers for Disease Control Medical Eligibility Criteria list combined oral contraceptives (COCs) as category 3 for women taking ritonavir-boosted protease inhibitors. This rating is based on small pharmacokinetic studies showing decreased levels of ethinyl estradiol in women taking protease inhibitors and COCs. The same studies have primarily demonstrated increased levels of progestins. No existing studies have examined the effects of protease inhibitors on a levonorgestrel-containing COC, nor have any prior studies rigorously assessed ovulation in women taking COCs and protease inhibitors. ❧ Objectives: Our primary objective is to determine the effects of ritonavir-boosted protease inhibitor use on the pharmacokinetics of levonorgestrel as compared to women taking regimens that do not interact with COCs. Secondary objectives include describing the effects of ritonavir-boosted protease inhibitors on ethinyl estradiol pharmacokinetics and to compare the prevalence of ovulation during COC use in women taking ritonavir-boosted protease inhibitors compared to women on regimens not interacting with COCs. ❧ Methods: This is a two-arm prospective cohort and steady-state pharmacokinetic study. We will recruit a total of 20 HIV-positive ovulatory women aged 18-45, including 10 women taking ritonavir-boosted protease inhibitors and 10 taking either no antiretroviral medication or regimens that have been found not to interact with COCs. Participants take a COC containing levonorgestrel and ethinyl estradiol daily for 21 days. During this period they undergo twice-weekly blood draws for serum progesterone levels. On day 21, they present for a pharmacokinetic visit and pharmacokinetic profiles for levonorgestrel and ethinyl estradiol are obtained. Levonorgestrel and ethinyl estradiol levels will primarily be assessed using area-under-the-curve from 0-72 hours (AUC). Maximum concentration (Cmax) and time to Cmax (Tmax) will be also be compared. Ovulation will be defined as any serum progesterone level greater than 3.0 ng/mL. ❧ Results: 18 women were screened, of whom 15 were eligible and completed the study, including 10 women in the control group and 5 women on ritonavir-boosted protease inhibitors. The control and protease inhibitor groups were demographically comparable. Preliminary results for the first 9 participants demonstrated an increase in levonorgestrel AUC of 38.7% in women taking protease inhibitors. Other pharmacokinetic parameters were similar between the groups. Data are not yet available for ethinyl estradiol pharmacokinetics. No women ovulated during the study. ❧ Conclusion: Preliminary data suggest no decrease in levonorgestrel pharmacokinetics and no change in ovulation suppression during combined oral contraceptive use in women on ritonavir-boosted protease inhibitors.

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Asset Metadata

Creator Barcellos, Teresa (author)

Core Title Effects of protease inhibitor use on combined oral contraceptive pharmacokinetics and pharmacodynamics in HIV-positive women

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 07/27/2016

Defense Date 07/25/2016

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

Tag combined oral contraceptives,contraception,HIV,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Bender, Nicole (committee chair), Azen, Stanley (committee member), Natavio, Melissa Faith (committee member)

Creator Email tbarcell@usc.edu,teresa.lynn.barcellos@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-280647

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