Clin Pharmacokinet

DOI 10.1007/s40262-014-0204-8

REVIEW ARTICLE

Pharmacokinetic and Pharmacodynamic Drug Interactions

Between Antiretrovirals and Oral Contraceptives
Victoria Tittle • Lauren Bull • Marta Boffito •

Nneka Nwokolo

Ó Springer International Publishing Switzerland 2014

Abstract More than 50 % of women living with HIV
in low- and middle-income countries are of reproductive
age, but there are limitations to the administration of oral
contraception for HIV-infected women receiving antiret-
roviral therapy due to drug–drug interactions caused by
metabolism via the cytochrome P450 isoenzymes and
glucuronidation. However, with the development of
newer antiretrovirals that use alternative metabolic
pathways, options for contraception in HIV-positive
women are increasing. This paper aims to review the
literature on the pharmacokinetics and pharmacodynam-
ics of oral hormonal contraceptives when given with
antiretroviral agents, including those currently used in
developed countries, older ones that might still be used
in salvage regimens, or those used in resource-limited
settings, as well as newer drugs. Nucleos(t)ide reverse
transcriptase inhibitors (NRTIs), the usual backbone to
most combined antiretroviral treatments (cARTs) are
characterised by a low potential for drug–drug interac-
tions with oral contraceptives. On the other hand non-
NRTIs (NNRTIs) and protease inhibitors (PIs) may
interact with oral contraceptives. Of the NNRTIs, ef-
avirenz and nevirapine have been demonstrated to cause
drug–drug interactions; however, etravirine and
V. Tittle and L. Bull are joint first author.
V. Tittle (&)  L. Bull  M. Boffito  N. Nwokolo
Department of GUM/HIV Medicine, St. Stephen’s Centre,
Chelsea and Westminster Hospital, 369 Fulham Road, London
SW10 9NH, UK
e-mail: marta.boffito@chelwest.nhs.uk
M. Boffito
Imperial College, London, UK
rilpivirine appear safe to use without dose adjustment.
PIs boosted with ritonavir are not recommended to be
used with oral contraceptives, with the exception of
boosted atazanavir which should be used with doses of at
least 35 lg of estrogen. Maraviroc, an entry inhibitor, is
safe for co-administration with oral contraceptives, as are
the integrase inhibitors (INIs) raltegravir and dolutegra-
vir. However, the INI elvitegravir, which is given in
combination with cobicistat, requires a dose of estrogen
of at least 30 lg. Despite the growing evidence in this
field, data are still lacking in terms of large cohort
studies, randomised trials and correlations to real clinical
outcomes, such as pregnancy rates, in women on anti-
retrovirals and hormonal contraception.
Key Points
Metabolism of hormonal contraceptives by
cytochrome P450 isozymes and uridine 50 -
diphosphate glucronosyltransferase isozymes causes
significant interactions with ritonavir- boosted
protease inhibitors and older non-nucleos(t)ide
reverse transcriptase inhibitors (NNRTIs).
Newer classes of antiretrovirals such as the more
recently developed NNRTIs, CC human chemokine
(CCR5) receptor antagonists and some integrase
inhibitors do not affect the pharmacokinetics of
steroid hormones and may be used with oral
hormonal contraceptives.
More research in large cohort studies involving HIV-
positive women with similar demographics would be
beneficial in the future to improve choice for women.
 V. Tittle et al.

1 Introduction progestogen. Progesterone-only pills, as their name

implies, contain fixed doses of progestogen without
estrogen.
Globally, there are an estimated 35.3 million people living
The progestogen component of combined pills has been
with HIV [1]. Women of reproductive age comprise 52 % of
under refinement over several decades resulting in different
all people living with HIV in low- and middle-income
‘generations’ of pills with differing progestogen metabo-
countries and 57 % in sub-Saharan Africa [1]. Additionally,
lites that have the desired anti-conception properties but
AIDS-related illnesses are the leading cause of death among
minimal androgenic adverse effects (Table 1). Progesto-
women of reproductive age [2]. Comprehensive reproduc-
gens are classified by their chemical structure, being either
tive healthcare including contraception is of vital importance
related to progesterone or testosterone.
to the overall health of women living with HIV; the physical
The number and types of cARTs and contraceptive pills
and mental consequences of an unintended pregnancy can be
have expanded in recent years and the aim of this review is
profound, particularly when compounded by living with
to outline what is currently known in the literature with
chronic disease. In the era of combined antiretroviral treat-
regard to the pharmacology and potential drug–drug
ment (cART), HIV has become a chronic manageable con-
interactions between these drugs and, thus, importantly,
dition and many more women are thus now in a position to re-
what implications this has for their efficacy. For the pur-
evaluate their reproductive choices including pregnancy
poses of this review, we focus on oral contraceptives,
planning and the use of hormonal contraception. It must also
specifically the combined pill and the progesterone-only
be noted that although there has been tremendous progress
oral pill, and, within this, the emergency oral contraception
towards reducing mother-to-child transmission, particularly
is also discussed.
in developed countries, this remains a significant route of
HIV transmission worldwide [3]. For this reason, effective
2.1 Metabolism of Oral Contraceptives
contraception and prevention of unintended pregnancy is a
crucial tool in the effort to reduce the risk of HIV acquisition
The estrogen and progestogens (some of which are ingested
in children, as well as helping to improve maternal morbidity
as inactive prodrugs) in oral contraceptives undergo
and reducing maternal death [1]. Globally, there remains a
extensive first-pass metabolism by phase I and II micro-
significant proportion of women living with HIV with an
somal enzymes in the small intestinal mucosa and liver
unmet need for contraceptive services [3], with as many as
before reaching the systemic circulation [7, 8]. Phase I
20 % of HIV-positive women in some countries expressing a
enzymes (mixed-function oxidases) catalyse oxidation,
wish to delay or stop childbearing but who are not using
reduction and hydrolysis, and phase II enzymes catalyse
contraception [3]. Unfortunately, the contraceptive choices
glucuronidation, sulphation and acetylation pathways [7–
available to HIV-positive women in both developed and
9]. The main pathway of metabolism for oral contracep-
developing countries are limited largely to intrauterine
tives is via the cytochrome P450 (CYP) isoenzyme 3A4
methods and barrier methods such as male and female con-
(CYP3A4), which is the major subtype in adult intestinal
doms because of significant drug–drug interactions between
mucosal cells and hepatocytes. Although most of the
certain antiretrovirals and hormonal contraceptives.
The current management of HIV infection involves the
administration of combinations of different classes of an- Table 1 The ‘generations’ of progesterone used in the combined oral
tiretrovirals. These agents target different parts of the HIV contraceptive pill
life cycle. Current guidelines recommend that therapy- First generation
naı̈ve patients start cART containing two nucleos(t)ide 1) Estranes derived from testosterone: norethindrone,
reverse transcriptase inhibitors (NRTIs) plus one of the norethynodrel, norethindrone acetate, ethynodiol diacetate
following: a non-NRTI (NNRTI), a ritonavir-boosted pro- 2) Pregnanes derived from 17-hydroxyprogesterone:
tease inhibitor (PI/r) or an integrase inhibitor (INI) [4–6]. medroxyprogesterone acetate, chlormadinone acetate
Second generation
Gonanes derived from testosterone: levonorgestrel, norgestrel
2 Oral Contraceptives Third generation
Gonane (levonorgestrel) derivatives: desogestrel, gestodene,
norgestimate/norelgestromine, etonorgestrel
Combined oral contraceptive pills are among the most
commonly used forms of contraception worldwide. The Fourth generation
majority of these pills are monophasic or fixed-dose pills 1) Non-ethylated estranes: dienogest, drospirenone
containing synthetic estrogen [usually ethinyl estradiol 2) Pregnanes (19-norprogesterones) nestorone, nomegestrol
acetate, trimegestone
(EE) in concentrations of between 20 and 35 lg] and a
DDIs Between Antiretrovirals and Oral Contraceptives

Table 2 Summary of pharmacokinetics of progestogens

Drug Bioavailability Protein Clearance Metabolism Inducer of Inhibitor of
(oral) (%) binding
(%)

Desogestrel [65, 66] 70 95.9–99 Urine, Hydroxylation; No data No data

bile, dehydrogenation;
faeces glucuronidation
CYP2C9; CYP3A4
Drosperinone [67–69] 76–85 95–97 Urine, Sulphation No data CYP3A4, CYP1A1,
faeces CYP3A4 (minor) CYP2C9 and
CYP2C19 in vitro
Etonogestrel [70–72] 70 95.5–99 Urine Hydroxylation; No data No data
reduction; sulphation;
glucuronidation
CYP3A4
Gestodene [73–75] 99 98–99 Urine, CYP3A4 No data Potent inhibitor of
bile CYP3A4 in vitro but
low doses used
clinically do not
inhibit CYP3A4
in vivo
Levonogestrel [74, 76] 100 98.5 Urine, Hydroxylation; No data CYP2C19 and CYP3A4
faeces glucuronidation (less significant than
other progestins) [73]
Norethisterone [74, 77, 78] 49–73 [95 Urine CYP3A4 No data CYP3A4 (modest)
Norgestimate (metabolised to 95–100 [97 Urine, CYP3A4 No data CYP3A4 (weak)
norelgestromin then faeces
levonorgestrel) [74, 79]
CYP cytochrome P450

metabolism of oral contraceptives occurs via CYP, the
glucuronidation pathway also plays a role.
2.2 Estrogen
EE is predominantly metabolised by CYP3A4 and CYP2C9,
with CYP2C8, CYP2C19 and CYP3A5 also playing a minor
role [9]. Glucuronidation by uridine 50 -diphosphate glucu-
ronosyltransferase (UGT) isoenzymes, particularly
UGT1A1, is also an important clearance pathway [10]. EE
has also been demonstrated in vitro to inhibit CYP2C19,
CYP3A4 and CYP2B6 [9]. There is evidence of a CYP3A4-
inducing effect by EE in rat models, but this is not thought to
be clinically relevant in humans. Metabolism of estrogen by
the isoenzymes described above results in interactions with
numerous medications including lamotrigine, topiramate,
carbamazepine, eslicarbazepine, oxcarbazepine, phenobar-
bital, primidone, phenytoin, St John’s wort, rifabutin and
rifampicin (rifampin) [11].
2.3 Progestogens
Most progestogens are prodrugs. They undergo hepatic
first-pass metabolism and the majority are substrates of
CYP3A4; however, there is variation in the metabolism of
these compounds with significant inter- and intra-individ-
ual variability [12, 13]. The characteristics of metabolism
of the main progestogen derivatives are outlined in
Table 2.
3 Metabolism of Antiretroviral Drugs
Of the different classes of antiretrovirals, NNRTIs and PIs
are implicated in the majority of drug–drug interactions.
However, it cannot be assumed that every drug in the same
class will have the same effect on metabolism. Interactions
involving NRTIs tend to be minimal because these drugs
have no effect on, and are not substrates for, CYP [14–26].
However, they may at times cause pharmacodynamic
interactions, leading to enhanced toxicities when used with
certain other drugs, e.g. tenofovir co-administration with
nephrotoxic agents [27]. Table 3 reports a detailed
description of the metabolic pathways of currently used
antiretrovirals.
Maraviroc, a CC human chemokine (CCR5) receptor
antagonist, is a substrate of CYP3A and P-glycoprotein (P-
gp). It has no significant inhibitory effect on CYP enzymes

and only a weak induction effect on CYP2D6, which is
unlikely to have clinically systemic effects. It does not
significantly affect P-gp [28] (Table 3).
The INI raltegravir is metabolised via UGT1A1-medi-
ated glucuronidation [29]. It is not a substrate of, nor does
it have any effect on, the CYP pathway. Thus, it has a low
potential for CYP-mediated pharmacokinetic interactions.
Dolutegravir is also primarily metabolised by UGT1A1
and, to a minor degree, by CYP3A and is a substrate of
UGT1A3, UGT1A9 and P-gp [29]. Elvitegravir is pre-
dominantly metabolised by CYP3A enzymes but also
undergoes glucuronidation by UGT1A1/3 enzymes; it acts
as a substrate for these as well as inducing CYP2D6 [29]
(Table 3).
Cobicistat has no antiretroviral activity; however, it is a
potent CYP3A4 inhibitor as well as inhibiting CYP2D6,
P-gp and other transporters, e.g. breast cancer resistance
protein (BCRP). It is currently part of a fixed-dose com-
bination tablet to boost concentrations of elvitegravir [29]
(Table 3).
4 Methodology and Research Results
A literature search was performed using the MEDLINE
(PubMed) database and conference searches. The follow-
ing search terms were used: HIV, women, female, oral
contraceptive, oral contraception, contraception, antiretro-
viral(s), hormonal contraception, hormonal contraceptive,
oestrogen, estrogen, progesterone, nucleotide reverse
transcriptase inhibitor, nucleoside reverse transcriptase
inhibitor, non-nucleotide reverse transcriptase inhibitor,
protease inhibitor, integrase inhibitor, fusion inhibitor,
darunavir, ritonavir, atazanavir, lopinavir, saquinavir, kal-
etra, etravirine, efavirenz, nevirapine, rilpivirine, raltegra-
vir, dolutegravir, elvitegravir, cobicistat, truvada,
tenofovir, emtricitabine, kivexa, abacavir, lamivudine,
zidovudine, combivir, stavudine, maraviroc, enfuvirtide,
didanosine, atripla, stribild, ethinyl estradiol, desogestrel,
gestodene, norethisterone, drospirenone, levonorgestrel,
norgestimate, mestranol, estradiol, nomegestrol, dienogest,
estradiol valerate and ulipristal.
Research papers on the pharmacokinetics of cART and
oral hormonal contraceptives, including emergency con-
traceptives, were reviewed. Other forms of contraception
were not included in this review paper. The following
conferences were reviewed for relevant abstracts: Euro-
pean AIDS Clinical Society, British HIV Association,
Conference on Retroviruses and Opportunistic Infections,
International AIDS Conference, Congress of the European
Society of Gynecology, International Workshop on Clini-
cal Pharmacology of HIV Therapy and the International
Congress on Drug therapy in HIV Infection.
V. Tittle et al.
5 Interactions with Nucleos(t)ide Reverse
Transcriptase Inhibitors (NRTIs)
Although NRTIs are the backbone of most antiretroviral
combinations for the treatment of HIV infection, to date
there is very limited research on the pharmacology of the
co-administration of these agents and oral contraceptives.
This is probably because NRTIs are not substrates/indu-
cers/inhibitors of CYP isoenzymes. Therefore, the potential
for drug–drug interactions between NRTIs and oral con-
traceptives is low.
Aweeka et al. [30] demonstrated no impact on the
concentration of zidovudine with EE 35 lg and norethin-
drone 1 mg, and Kearney and Mathias [31] showed the
lack of an interaction between tenofovir and EE/
norgestimate.
6 Interactions with Non-NRTIs
NNRTIs act as both inducers and inhibitors of various CYP
enzymes and this is demonstrable in the evidence pertain-
ing to their effect on hormonal contraceptive efficacy. In
the following sections, the NNRTIs are discussed in order
of their development.
6.1 Nevirapine
Nevirapine acts as an inducer of the CYP3A4 enzyme and
therefore typically diminishes concentrations of similarly
metabolised drugs. A clinical trial performed in 2002
enrolled ten HIV-infected women on stable cART. In
addition to their background antiretrovirals, they were
given a single dose of EE/norethindrone on day 1 and day
30, whilst nevirapine was given as follows: 200 mg once
daily on days 2–15, followed by 200 mg twice daily on
days 16–29 with a single additional dose on day 30. The
study found that concurrent use of nevirapine and EE/
norethindrone resulted in a significant 29 % median
reduction in the area under the plasma concentration–time
curve (AUC) and a significant reduction in the mean
residence time (MRT) and half-life (t‘) of EE. There was
also an 18 % median reduction in the AUC of norethin-
drone but no detectable change in norethindrone maxi-
mum concentration (Cmax), MRT or t‘ [32]. The
nevirapine package insert reports the presence of a sig-
nificant interaction between nevirapine and oral contra-
ceptives [33]. Furthermore, a recent study by Landolt
et al. [34] demonstrated a significant decrease in EE with
nevirapine, and in etonogestrel with efavirenz in HIV-
positive women, although serum progesterone remained
suppressed in the nevirapine group, consistent with
maintenance of anovulation.
Table 3 Summary of pharmacokinetics of antiretrovirals
Drug Bioavailability Protein Renal clearance Metabolism [29] Inducer of [29] unless Inhibitor of Transported by
(%) [29] binding (%) [29] unless otherwise stated otherwise stated
(%) [29]

Nucleos(t)ide reverse transcriptase inhibitors

Abacavir 83 *49 \2 Alcohol No hepatic enzyme BCRP (in vitro); MRP1, MRP2 [80, 81] P-gp; BCRP1
dehydrogenase; UGT induction [82, 83]
Emtricitabine 93 (hard \4 *86 Limited hepatic Low potential for hepatic MRP1, MRP2, MRP3 [81]. Low potential for None [84]
capsule) metabolism (UGT) enzyme induction hepatic enzyme inhibition
75 (oral
solution)
Lamivudine 80–85 \36 [70 Limited hepatic No hepatic enzyme MRP1, MRP2, MRP3 [81] MRP4, MRP8
metabolism induction (in vitro) [85]
(5–10 %)
Tenofovir *25 \0.7 32 ± 10 when taken with Not a substrate for No hepatic enzyme MRP1, MRP2, MRP3 [81] OAT 1 and 3;
food CYP; eliminated induction MRP4
unchanged
DDIs Between Antiretrovirals and Oral Contraceptives

Zidovudine 60–70 34–38 Significant tubular secretion UGT (to inactive No hepatic enzyme BCRP (in vitro) [80] BCRP [83]
metabolite) induction
Non-nucleos(t)ide reverse transcriptase inhibitors
Nevirapine 93 *60 \3 CYP3A4, CYP2B6 CYP3A4, potentially BCRP (in vitro) [80]; MRP1, MRP2, MRP3 Unknown
CYP2B6 [81]
Efavirenz Data not [99 \1 CYP3A4, CYP2B6 CYP3A4 CYP2C9, CYP2C1, CYP3A4; BCRP (in vitro) Unknown
available [80]; MRP1, MRP2, MRP3 [81]
Etravirine Data not 99.9 \1.2 CYP3A4, CYP2C9, CYP3A4 CYP2C9, CYP2C19 [29] Unknown
available CYP2C19
Rilpivirine Data not 99.7 \1 CYP3A, CYP2A19 No hepatic enzyme P-gp (possible) [86] P-gp (not
available (potential) [84] induction significant)
[86]
PIs
Ritonavira Data not 98–99 3.5 CYP3A, CYP2D6 CYP1A2, CYP2C8, CYP3A, CYP2D6; P-gp [81]; MRP1 [83]; P-gp [89];
available CYP2C9, CYP2C19; OATP-C [87]; BCRP [88] MRP1 [90]
MRP1 [86]
Atazanavir *68 *86 7 CYP3A4 P-gp; MRP1 [88] CYP3A4, CYP2C8; UGT1A1; P-gp; BCRP P-gp; MRP;
[91]; MRP [92]; OATP [93] BCRP [92]
Darunavir 37 (alone) *95 7.7 (boosted with ritonavir) CYP3A4 CYP2C9, CYP2C19, CYP3A4, CYP2D6; P-gp; OATP [93] P-gp [94]
82 (boosted CYP2C8 (in vitro)
with
ritonavir)
Lopinavir Data not 98–99 \3 CYP3A No hepatic enzyme CYP3A; BCRP (in vitro) [80] P-gp; MRP1,
available induction MRP2; OATP
[95]
 V. Tittle et al.

Surprisingly, however, subsequent research has shown

BCRP breast cancer resistance protein, CYP cytochrome P450, MRP multidrug resistance protein, OAT organic anion transporter, OATP organic anion-transporting polypeptide, OCT organic cation
Transported by

P-gp (minor)

BCRP; P-gp
data for the interaction between nevirapine and oral con-

Unknown
P-gp [84]
traceptives that contradicts the studies described above. In

[84]

[84]
a small study of nine women, Stuart et al. [35] found that
EE and levonorgestrel concentrations were higher in HIV-
infected women, including those taking antiretrovirals

Cobicistat: CYP3A (strong), CYP2D6 (weak);

No significant hepatic enzyme inhibition [29]
No significant hepatic enzyme inhibition but
potential inhibition of CYP2D6 in higher
(mainly nevirapine-containing cART), than in HIV-nega-

P-gp, BCRP; OATP1B1, OAT1B3 [84]

tive women in Malawi, and a non-randomised prospective
clinical trial examined the effectiveness of EE 30 lg/nor-
gestrel 300 lg in 196 HIV-infected women taking nevira-
pine compared with 206 treatment-naı̈ve HIV-infected
women in Uganda and South Africa. This trial involved

OCT2 (in vitro) [84]

weekly progesterone measurements to estimate ovulation,
and pregnancy tests were performed monthly. The results
demonstrated no significant differences in ovulation or
doses [84]
Inhibitor of

pregnancy rates between the group on oral contraceptives

and nevirapine and the group just on oral contraceptives
[36]. This is one of very few trials with a clinical outcome
endpoint. These important findings challenge the current
Inducer of [29] unless

Elvitegravir: CYP2C9
No significant hepatic

dogma that oral contraceptives are not effective when used

enzyme induction

No hepatic enzyme

No hepatic enzyme

concomitantly with nevirapine. However, further data on

(modest); UGT
otherwise stated

HIV-infected women using antiretrovirals and oral con-

induction

induction
(modest)

traceptives from real-life settings are warranted to confirm

these findings.
Ritonavir and cobicistat are used to boost concentrations of protease inhibitors and elvitegravir, respectively

6.2 Efavirenz
unless otherwise stated

UGT; CYP3A (minor)

Elvitegravir: CYP3A,

Cobicistat: CYP3A,
CYP2D6 (minor)

Early studies suggested that efavirenz affects EE concen-

Metabolism [29]

trations in different, unexpected, ways: for example, a

UGT1A1

37 % increase in EE AUC was shown after a single dose of

CYP3A4

UGT

EE 50 lg given to 13 HIV-negative subjects on efavirenz

transporter, P-gp P-glycoprotein, UGT uridine diphosphate glucuronosyltransferase

for 10 days [37]. However, it is thought this may have

resulted from interference with the estradiol ELISA assay
*8 (can increase to 70 % if

causing an artificial elevation in serum concentrations of

Minor renal excretion
metabolic inhibitors

estradiol [38]. Efavirenz acts as a CYP3A4 inducer, and in

a study in which 28 HIV-negative women were given
Renal clearance

600 mg of efavirenz daily for 14 days and EE 35 lg/

present)

norgestimate 0.25 mg daily, although there was no signif-

(%) [29]

icant alteration in EE concentrations, efavirenz lowered the

32

31

17-deacetyl norgestimate (the active metabolite of norg-

estimate) AUC by 64 %, Cmax by 46 % and minimum
(%) [29]

concentration (Cmin) by 82 % [39]. Importantly, the clini-

binding
Protein

C98.9
98–99
*76

*83

cal significance of these effects is unclear; therefore, it is

recommended that additional reliable methods of barrier
contraception are used with oral hormonal contraceptives.
Bioavailability

23 (100 mg

available

available

available
Data not

Data not

Data not
(%) [29]

6.3 Etravirine
dose)
Table 3 continued

Integrase inhibitors

In 2009, Schöller-Gyüre et al. [40] demonstrated no sig-

Entry inhibitors

Dolutegravir
Elvitegravir/

nificant interactions between etravirine and EE/norethin-

Raltegravir

cobicistata
Maraviroc

drone. Thirty HIV-negative women received three cycles

of EE 35 lg and norethindrone 1 mg daily. In cycle 2, EE
Drug

and norethindrone concentrations were measured on day

a
DDIs Between Antiretrovirals and Oral Contraceptives
15, and in cycle 3 etravirine was administered on days
1–15. On day 15 the pharmacokinetics of EE, norethin-
drone and etravirine were assessed. With etravirine, the
least-squares mean (LSM) ratios (90 % confidence inter-
vals [CIs]) for EE AUC, Cmax and Cmin were 1.22
(1.13–1.31), 1.33 (1.21–1.46) and 1.09 (1.01–1.18),
respectively, compared with administration alone. LSM
ratios for norethindrone parameters were 0.95 (0.90–0.99),
1.05 (0.98–1.12) and 0.78 (0.68–0.90), respectively.
Therefore, etravirine can be co-administered with oral
contraceptives containing 35 lg of EE; however, data on
other doses of EE are not available.
6.4 Rilpivirine
The newest of the NNRTIs was studied in an open-label
prospective trial involving 18 HIV-negative women [41].
The women were given EE 35 lg/norethindrone 1 mg
once daily for three sequential cycles. In the third cycle,
rilpivirine 25 mg daily was given on days 1–15. Phar-
macokinetic assessment was performed on day 15 of
both the second and third cycles. The results (LSM ratio
[90 % CI]) demonstrated that rilpivirine co-administra-
tion had no effect on EE Cmin (1.09 [1.03–1.16]) or
AUC (1.14 [1.10–1.19]), but increased its Cmax by 17 %
(1.17 [1.06–1.30]). Rilpivirine was therefore deemed
unlikely to affect EE pharmacodynamics. Norethindrone
pharmacokinetics were equally unaffected by rilpivirine
(AUC: 0.89 [0.84–0.94]; Cmin: 0.99 [0.90–1.08]; Cmax:
0.94 [0.83–1.06]). Additional analysis showed that the
steady-state rilpivirine pharmacokinetics with EE/noreth-
indrone were comparable with historical data for rilpiv-
irine alone. Thus, it is concluded that no dose
modification is required in the co-administration of these
drugs.
7 Interactions with Protease Inhibitors (PIs)
Today, in clinical practice, PIs are co-administered with
low doses of ritonavir (100 mg either once or twice daily)
to ensure the achievement of optimal drug exposure and
therefore efficacy via CYP3A4 metabolism inhibition.
However, importantly, the impact of a boosted PI has a
significant effect on the metabolism of other medications,
including oral hormonal contraceptives.
7.1 Ritonavir
Aside from its impact on the CYP isoenymes, ritonavir also
induces UGT, causing complex interactions between
boosted PIs and oral contraceptives [42, 43].
7.2 Atazanavir
As well as being a substrate for CYP3A4, atazanavir is also
an inhibitor of UGT, resulting in differing effects on con-
traceptive steroid concentrations when boosted with riton-
avir or given on its own.
Tackett et al. [44] studied 22 healthy female volunteers
who were given EE/norethindrone from day 1 to day 29
and unboosted atazanavir (400 mg) from day 16 to day 29,
resulting in an 110 % increase in AUC for norethindrone
and 48 % increase in AUC for EE.
However, a more recent study of ritonavir-boosted at-
azanavir (atazanavir/r; 300/100 mg once daily) with Ortho
Tri-CyclenÒ LO (Janssen Pharmaceuticals, Inc., Titusville,
NJ, USA) (EE 35 lg ? norgestimate 0.18/0.215/0.25 mg)
[45] in 20 healthy women, found a reduction of 16 % in the
Cmax, 19 % in the AUC and 37 % in the Cmin of EE. This
effect may be explained by the fact that the increase in
exposure of atazanavir caused by ritonavir (which would
be expected to increase the AUC of EE) is countered by
ritonavir’s concomitant induction of glucuronidation,
resulting in a smaller than expected increase in EE con-
centration. Progestogen concentrations were increased in
both studies, likely as a result of increased atazanavir
exposure, since boosted PIs appear to have a much less
significant effect on progestogen [46]. The authors rec-
ommend that combined pills containing no less than 30 lg
of EE be used in women taking boosted atazanavir. The
clinical significance of the increased progestogen exposure
is unclear.
7.3 Darunavir and Lopinavir
The use of ritonavir-boosted darunavir (darunavir/r) with
combined oral hormonal contraceptives is not recom-
mended, as both EE and norethindrone concentrations have
been found to be decreased when used with darunavir/r. In
the study by Sekar et al. [47], 19 healthy female volunteers
were recruited and 11 completed the study. Women were
given EE 35 lg and norethindrone 1 mg for 42 days and
darunavir/r on days 22–35 with blood samples taken on
days 14 and 35. The significant reduction in EE (Cmin
62 %, Cmax 32 % and AUC 44 %) and in norethindrone
(Cmin 30 %, Cmax 10 % and AUC 14 %) differ from the
results of studies on other PIs where the progesterone
component seems not to be affected. Reductions in EE
have also been found with ritonavir-boosted lopinavir
(lopinavir/r), resulting in a 55 % decrease in AUC,
although with no significant changes to progesterone con-
centrations [48]. In conclusion, the interaction of PI/r with
combined oral contraceptives is complex and variable.
Although a higher dose of EE (35 lg) with atazanavir/r

may be acceptable, oral contraceptives should not be used
with darunavir/r or lopinavir/r.
7.4 Effect of PIs on Progestogen-Only Oral
Contraceptives
Most research on drug–drug interactions between antiret-
rovirals and hormonal contraceptives has been performed
on women taking the combined oral contraceptive pill and
there is a paucity of data on the effects of antiretrovirals on
progestogen-only contraception.
In a recent study of 33 HIV-seropositive women to
compare the steady-state pharmacokinetics of norethin-
drone in women receiving a variety of PI- and non-PI-
containing cART regimens, subjects were given norethin-
drone 0.35 mg for 21 days in addition to their antiretrovi-
rals. Plasma concentrations of norethindrone were
measured on or after day 22. The study showed a 50 %
increase in the norethindrone AUC in women on PIs
compared with those on non-PI regimens with no differ-
ence in norethindrone t‘ between the groups. The authors
state that this is likely to be due to the inhibitory effect of
PIs on CYP3A4, of which norethindrone is a substrate [46].
8 Entry Inhibitors
As previously discussed, maraviroc is not thought to have
any significant clinical impact on CYP3A or P-gp and,
therefore, no significant effect on the metabolism of other
drugs. In a study aimed at reviewing the pharmacokinetics
of maraviroc with EE 30 lg/levonorgestrel 150 lg, 15
healthy Caucasian women were given maraviroc (300 mg
twice daily) or placebo for days 1–11 and EE/levonorge-
strel on days 2–8. Results showed that the Cmax, AUC and
Cmin of EE and levonorgestrel were similar when measured
with or without maraviroc, suggesting doses of 30 lg of
EE would be safe to use [49].
9 Integrase Inhibitors
Raltegravir is not a substrate of CYP and is characterised
by a low potential for drug–drug interactions. Anderson
et al. [50] studied the interaction between raltegravir with
Tri-CyclenÒ (EE 35 lg and increasing doses of norgesti-
mate at 0.180/0.215/0.35 mg) in a placebo-controlled
crossover study in 20 HIV-negative women. Women were
given raltegravir 400 mg twice daily or placebo with Tri-
CyclenÒ on days 1–21. Blood sampling for drug concen-
tration measurement was undertaken on day 21. Impor-
tantly, there was no difference in oral contraceptive
pharmacokinetics (AUC) when Tri-CyclenÒ was given
V. Tittle et al.
alone compared with when it was co-administered with
raltegravir [EE with raltegravir to EE alone: geometric
mean ratio (GMR) 0.98, 95 % CI 0.93–1.04; and for
17-deacetyl norgestimate with raltegravir to 17-deacetyl
norgestimate alone: GMR 1.14, 95 % CI 1.08–1.21].
A study looking at StribildÒ (elvitegravir/cobicistat/
tenofovir/emtricitabine) (Gilead, Foster City, CA, USA)
with EE 25 lg and norgestimate 0.180/0.215/0.250 mg
found a reduction in EE Cmax of 6 % and AUC of 25 %,
with a two-fold increase in AUC with 17-deacetyl norg-
estimate and no alteration in the concentrations of sex
hormones (serum progesterone, follicle-stimulating hor-
mone, luteinizing hormone) with or without StribildÒ [51].
Therefore, researchers recommend at least an EE 30 lg
dose with StribildÒ.
Finally, in a randomised, placebo-controlled crossover
study, female healthy volunteers were given EE 35 lg and
norgestimate 0.25 mg and dolutegravir 50 mg twice daily
for 10 days and then switched so that those who had taken
dolutegravir received placebo and vice versa for 10 days.
The LSM ratios (95 % CI) of AUC and Cmax for EE with
dolutegravir against placebo were 1.03 (0.964–1.11) and
0.98 (0.907–1.08), respectively, and for 17-deacetyl norg-
estimate were 0.975 (0.910–1.04) and 0.890 (0.815–0.973),
respectively. Furthermore, luteinizing hormone, follicle-
stimulating hormone and progesterone concentrations on
days 1, 10, 11, 21 and 22 did not differ between the
dolutegravir and placebo arms, supporting the use of
combined oral contraceptives with dolutegravir [52]. The
use of oral combined contraceptives is promising with
INIs, and this class of antiretrovirals could provide HIV-
infected women with a wider range of choice in their
contraceptive needs.
10 Emergency Contraception
Oral emergency contraception exists in the form of levo-
norgestrel, a synthetic progestogen, and ulipristal acetate
(UPA), a selective progesterone receptor modulator. The
precise mechanism of action of levonorgestrel is not well
understood but is thought to be by inhibiting ovulation by
preventing follicle rupture or causing luteal dysfunction
[53–58]. The primary mechanism of action of UPA is
thought to be inhibition or delay of ovulation by sup-
pressing follicle growth [59] or follicle rupture [60], and
also possibly by delaying endometrial maturation [61].
There is a relative paucity of data on the effect of an-
tiretrovirals on the hormone concentrations in emergency
contraception. The current recommendation for women
taking any enzyme-inducing drug is to double the dose of
levonorgestrel to 3 g; however, this remains off-label [13].
The only study performed with levonorgestrel was a single-
DDIs Between Antiretrovirals and Oral Contraceptives
arm prospective pharmacokinetic study on 21 HIV-nega-
tive women comparing levonorgestrel alone and levo-
norgestrel with efavirenz. This demonstrated a 56 % (95 %
CI 49–62) reduction in AUC and 41 % reduction in Cmax in
the presence of efavirenz. The study concluded that ef-
avirenz significantly lowered levonorgestrel exposure and
thus higher doses may be required [62]. To date, there are
no data on UPA with antiretrovirals. However, an inter-
action should be expected with all boosted PIs, efavirenz,
nevirapine and possibly etravirine, while it may be less
likely with rilpivirine, maraviroc or raltegravir [29, 63]
given that UPA is predominantly metabolised by CYP3A4.
Current recommendations state that in the absence of data,
UPA should not be given at double dose, and that it should
not be used by women using enzyme-inducing drugs or
who have stopped them within the last 28 days [61, 63].
11 Conclusions
Drug–drug interactions between oral contraceptives and
antiretrovirals are complex and, when significant, limit the
choices available to women to prevent conception.
Importantly, newer antiretrovirals such as rilpivirine,
raltegravir, and dolutegravir, which have a low potential
for drug–drug interactions, have become available over the
past few years. When indicated, these agents can be co-
administered safely with most doses of oral contraceptives.
However, issues of cost dictate that in many developed
countries new-generation antiretrovirals are not prescribed
to all and are kept for second-line therapy, rather than used
as first-line treatment in antiretroviral-naı̈ve individuals.
The arrival of these newer compounds signals that it is time
for a rethink about the management of HIV-positive
women who for decades have been sorely disadvantaged
compared to HIV-negative women with regard to their
contraceptive choices. It is important, therefore, that phy-
sicians are allowed to choose, where possible, antiretroviral
regimens that do not interact with hormonal contraceptives.
The ability to tailor antiretroviral regimens to take into
account current and future contraception will allow HIV-
positive women to have virtually the same contraceptive
choices as their HIV-negative counterparts. The cost of
providing effective, safe contraception to HIV-positive
women on treatment must be weighed against the costs
(physical, psychological as well as economic) that arise as
a consequence of unwanted pregnancy, including maternal
death and unsafe abortion.
Unfortunately, since the newer antiretrovirals mentioned
above are still unavailable in the developing world, where
two NRTIs plus nevirapine or efavirenz are the first-line
regimens of choice [64], there is no immediate prospect of
effectively prescribing oral contraceptives to the majority
of women worldwide living with HIV. Additionally,
tuberculosis, malaria and hepatitis B and C co-infection
with HIV are prevalent globally, resulting in potential
polypharmacy for vast numbers of patients. Many of the
treatments for these conditions share metabolic pathways
with the risk of significant drug–drug interactions. Fur-
thermore, these drugs have the potential to significantly
interact with oral contraceptives, adding to the complexity
of, and providing further challenges to, the management
women with HIV.
Acknowledgments No sources of funding were used to assist in the
preparation of this review. Marta Boffito has received travel and
research grants from and has been an adviser for Janssen, Roche,
Pfizer, ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme, Bo-
ehringer Ingelheim, AbbieVie and Gilead. Lauren Bull has received
sponsorship from Gilead to attend the BASHH (British Association
for Sexual Health and HIV) conference in 2012 and BHIVA (British
HIV Association) 2013, and received sponsorship from Janssen to
attend the BASHH conference in 2013. Victoria Tittle has received
payment by Gilead for organising an educational evening for junior
doctors, and sponsorship from Gilead to attend BHIVA 2012 and
EACS (European AIDS Clinical Society) 2011. Nneka Nwokolo has
no conflicts of interest to declare.
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