Drug interactions between hormonal contraceptives
and antiretrovirals
Kavita Nanda
a
, Gretchen S. Stuart
b
, Jennifer Robinson
c
,
Andrew L. Gray
d
, Naomi K. Tepper
e
and Mary E. Gaffield
f
Objective:
To summarize published evidence on drug interactions between hormonal
contraceptives and antiretrovirals.
Design:
Systematic review of the published literature.
Methods:
We searched PubMed, POPLINE, and EMBASE for peer-reviewed
publi-cations of studies (in any language) from inception to 21 September 2015. We included
studies of women using hormonal contraceptives and antiretrovirals concurrently.
Outcomes of interest were effectiveness of either therapy, toxicity, or pharmacokinetics.
We used standard abstraction forms to summarize and assess strengths and weaknesses.
Results:
Fifty reports from 46 studies were included. Most antiretrovirals whether used
for therapy or prevention, have limited interactions with hormonal contraceptive
methods, with the exception of efavirenz. Although depot medroxyprogesterone
acetate is not affected, limited data on implants and combined oral contraceptive pills
suggest that efavirenz-containing combination antiretroviral therapy may compromise
contraceptive effectiveness of these methods. However, implants remain very effective
despite such drug interactions. Antiretroviral plasma concentrations and effectiveness
are generally not affected by hormonal contraceptives.
Conclusion:
Women taking antiretrovirals, for treatment or prevention, should not be
denied access to the full range of hormonal contraceptive options, but should be
counseled on the expected rates of unplanned pregnancy associated with all
contra-ceptive methods, in order to make their own informed choices.
CopyrightQ2017 The Author(s). Published by Wolters Kluwer Health, Inc.
AIDS
2017,
31
:
917–952
Keywords: antiretroviral therapy, contraceptive implant, depot
medroxyprogesterone acetate, HIV, hormonal contraception, systematic review
Introduction
Women living with HIV will likely take combination
antiretroviral therapy (cART) for much of their lives [1].
Those at high risk for HIV may also use antiretrovirals for
preexposure prophylaxis (PrEP). Contraceptive use
among women living with HIV or using antiretrovirals
for PrEP is critical, as unintended pregnancy and short
interpregnancy intervals can be associated with negative
health consequences for both mother and infant [2–4].
Decreasing unintended pregnancies also reduces vertical
HIV transmission [5]. Hormonal contraceptives are
highly used worldwide, including in areas of high HIV
prevalence; they are also among the most effective
contraceptive methods [6,7]. Evidence-based guidance
for hormonal contraceptives use among women using
cARTor PrEP is needed to ensure access to a full range of
the best contraceptive methods, and therefore increase the
likelihood of achieving their reproductive life planning
goals.
a
FHI 360, Durham,
bUniversity of North Carolina Medical School, Chapel Hill,
cJohns Hopkins University School of Medicine,
Baltimore, Maryland, USA,
dDivision of Pharmacology, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal,
Durban, South Africa,
eDivision of Reproductive Health, U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, USA,
and
fDepartment of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
Correspondence to Dr Kavita Nanda, FHI360. 359 Blackwell Street, Durham, NC 27709, USA.
E-mail: [email protected]
Received: 5 September 2016; revised: 20 December 2016; accepted: 21 December 2016.
DOI:10.1097/QAD.0000000000001392
ISSN 0269-9370 CopyrightQ2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under
the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided
Concurrent use of hormonal contraceptives and
anti-retrovirals can lead to drug interactions, predominantly
due to effects on liver metabolism (Tables 1 and 2). In the
liver, cytochrome P450 (CYP) enzymes catalyze many
important reactions, with the most significant for
contraceptive metabolism being CYP3A4, which is also
expressed in the intestines [8,9]. Antiretrovirals include
different classes of drug (Table 2), including
nonside reverse transcriptase inhibitors (NNRTIs),
nucleo-side
analogue
reverse
transcriptase
inhibitors
or
nucleotide
analogue
reverse
transcriptase
inhibitor
(NRTIs), protease inhibitors, fusion inhibitors, and
integrase inhibitors. The NNRTIs and integrase
inhibi-tors are generally not substrates, inhibiinhibi-tors, nor inducers
of cytochrome P450 enzymes [10]. In contrast, both
protease inhibitors and NNRTIs are metabolized by
CYP3A4 and also inhibit or induce this enzyme, resulting
in increases or decreases in the concentration of
concomitantly administered drugs [10].
Such interactions could lead to decreased contraceptive
effectiveness (increasing risk of unintended pregnancy),
decreased cART effectiveness (associated with resistance
and/or HIV disease progression), decreased efficacy of
PrEP (increasing risk of HIV acquisition), or increased
antiretroviral or contraceptive toxicity. Based on
theor-etical concerns and limited data, women using cART are
sometimes offered fewer contraceptive choices than their
HIV-negative peers [11]. The objective of this review was
to systematically examine published evidence on drug
interactions between hormonal contraceptives and
antiretrovirals, in order to contribute to improved clinical
and policy decision-making.
Methods
We followed the PRISMA and MOOSE guidelines for
conducting the review and reporting the results [12,13].
We searched PubMed, POPLINE, and EMBASE from
database inception to 21 September 2015 for studies of
hormonal contraceptive and antiretroviral drug
inter-actions (Supplement 1, http://links.lww.com/QAD/
B36). We also hand-searched reference lists of published
studies, and contacted topic experts.
Study selection
We included published studies of women using hormonal
contraceptives (Table 1), including combined oral
contraceptives (COCs), progestin-only pills (POPs),
emergency contraceptive pills (ECPs), injectables, vaginal
rings, patches, or implants. Studies included women who
were either HIV-positive, HIV-negative but at risk of
HIV, or healthy, who concurrently used cART, PrEP, or
single antiretrovirals and hormonal contraceptives. We
included studies reporting on women taking oral
contraceptives where the type of oral contraceptive was
not specified. We excluded studies evaluating women on
cART without comparisons by contraceptive use, those
evaluating only genital HIV viral load, and those
Table 1. Steroids used in currently available contraceptive methods, their liver metabolism, and effects on liver enzymes.Contraceptive steroid Abbreviation Contraceptive method type (s) Metabolism
Estrogens
Ethinyl estradiol EE COC, patch, ring Inhibits CYP2C19, CYP3A4, and CYP2B6
Induces UGTs
Metabolized by CYP3A4 and CYP 2C9 and UGT
Estradiol cypionate E2C CIC Inhibits CYP2C19, CYP3A4, and CYP2B6
Induces UGTs
Metabolized by CYP3A4 and CYP 2C9 and UGT
Estradiol valerate E2V COC Inhibits CYP2C19, CYP3A4, and CYP2B6
Induces UGTs
Metabolized by CYP3A4 and CYP 2C9 and UGT Progestins
Ethynodiol diacetate EDA COCs Metabolized to norethindrone
Dienogest DNG COC Metabolized by CYP3A4
Nomegestrol acetate NOMAC COC Metabolized by CYP3A3, CYP3A4, and CYP2A6
Drospirenone DRSP COC Metabolized only to a minor extent, by CYP3A4
Gestodene GES COC Metabolized by CYP3A4
Norgestrel NG COC Metabolized by CYP3A4
Norgestimate NGM COC Metabolized by CYP3A4
Desogestrel DSG COC, POP Metabolized by CYP2C9 and CYP3A4
Norethindrone, norethindrone acetate NET COC, POI, POP Metabolized by CYP3A4 Norethisterone enanthate
Levonorgestrel LNG COC, implant, IUD, ECP Metabolized by CYP3A4
Norelgestromin NGMN Patch Metabolized by CYP3A4
Etonogestrel ENG Ring, implant Metabolized by CYP3A4
Medroxyprogesterone acetate MPA CIC, POI Metabolized by CYP3A4
Table 2. Antiretrovirals included in the review, their liver metabolism, and effects on liver enzymes.
Generic name Liver metabolism
NNRTIs
Efavirenz (EFV) Induces CYP3A4, CYP2B6, and UGTs
Metabolized by CYP2B6 and CYP3A
Etravirine (ETR) Induces CYP3A and inhibits CYP2C9, CYP2C19
Metabolized by CYP3A, CYP2C9, and CYP2C19
Nevirapine (NVP) Induces CYP3A and CYP2B6
Metabolized by CYP3A, CYP2B6, and UGTs
Rilpivirine (RPV) At higher doses (>3approved 25 mg dose), induces CYP3A4
Metabolized by CYP3A4, CYP2C19, CYP1A2, and CYP2C
Delavirdine (DLV) Inhibits CYP3A, CYP3A4, CYP2C9, CYP2D6, and CYP2C19
Metabolized by CYP3A and CYP2D6
Fosdevirine/GSK GSK2248761a Weak inhibitor of CYP3A4 and CYP2D6
Metabolized by CYP3A4? NRTIs
Zidovudine (ZDV) or azidothymidine (AZT) Does not affect liver enzymes Metabolized by UGTs
Abacavir (ABC) Does not affect liver enzymes
Metabolized by alcohol dehydrogenase and UGTs Tenofovir disoproxil fumarate (TDF) Does not affect liver enzymes
Minimal liver metabolism; mostly eliminated unchanged in urine
Emtricitabine (FTC) Does not affect liver enzymes
Minimal liver metabolism; mostly eliminated unchanged in urine
Didanosine (DDI) Does not affect liver enzymes
Minimal liver metabolism; mostly eliminated unchanged in urine
Lamivudine (3TC) Does not affect liver enzymes
Minimal liver metabolism; mostly eliminated unchanged in urine
Stavudine (d4T) Does not affect liver enzymes
Minimal liver metabolism; mostly eliminated unchanged in urine PIs
Ritonavir (RTV) Induces and inhibits CYP3A
Induces CYP1A2, CYP2C9, CYP2C19, CYP2B6, and UGTs Inhibits CYP2D6
Metabolized by CYP3A, CYP2D6
Atazanavir (ATV) Inhibits CYP3A and UGT1A1, and weak inhibitor of CYP2C8
Mostly metabolized by CYP3A4; other pathways include UGTs
Darunavir (DRV) Co-administered with ritonavir, inhibits CYP3A and CYP2D6
Mostly metabolized by CYP3A
Fosamprenavir (FOS-APV) Amprenavir, the active metabolite, induces and inhibits CYP3A4 Metabolized by CYP3A4
Saquinavir (SQV) Co-administered with ritonavir, inhibits CYP3A
Metabolized by CYP3A
Tipranavir (TPV) Co-administered with ritonavir, inhibits CYP3A and CYP2D6
Induces CYP1A2 and CYP2C19 at steady state Metabolized by CYP3A
Indinavir (IDV) Inhibits CYP3A4
Weak inhibitor of CYP2D6 Metabolized by CYP3A4
Nelfinavir (NFV) Inhibits CYP3A4
Metabolized by CYP3A, CYP2C19 CCR5 inhibitors
Maraviroc (MVC) Inhibits CYP2D6 at higher doses
Metabolized by CYP3A
Vicriviroc (VCV)a Does not affect liver enzymes
Metabolized by CYP3A Fusion inhibitors
Enfuvirtide (ENF) Does not affect liver enzymes
Catabolized to constituent amino acids Integrase inhibitors
Dolutegravir (DTG) Not an inducer or inhibitor of CYP enzymes
Metabolized by UGTs and CYP3A
Elvitegravir (EVG) Inducer of CYP2C9
Metabolized by CYP3A4
Raltegravir (RAL) Not an inducer or inhibitor of CYP enzymes
Metabolized by UGTs Pharmacokinetic enhancers
Cobicistat (COBI) Inhibits CYP3A, CYP2D6
Metabolized by CYP3A
Data from prescribing information, http://medicine.iupui.edu/clinpharm/ddis/main-table, and https://aidsinfo.nih.gov/drugs. CYP, cytochrome P450 isozyme; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside or nucleotide reverse-transcriptase inhibitor; PI, protease inhibitor; UGT, uridine diphosphate glucuronosyltransferase.
evaluating only hormonal intrauterine devices (IUDs).
We also excluded case or case-series reports,
cross-sectional studies, reviews, editorials, and letters.
Outcomes of interest were clinical and pharmacokinetic
measures of the contraceptive and the antiretroviral.
Clinical outcomes included measures of contraceptive,
cART, or PrEP effectiveness, and combined toxicity.
Contraceptive effectiveness measures of interest were
pregnancy or surrogate measures of pregnancy risk,
including ovulation, ovarian activity, or cervical mucus.
Because no studies reported on true ovulation as
documented by ultrasound, we included studies using
serum progesterone alone as a marker of presumed
ovulation. For cART effectiveness, we included studies
that reported markers of HIV disease progression such as
CD4
þcell count or HIV viral load, need for change in
cART regimen, or death; for PrEP effectiveness, the
relevant outcome was HIV prevention. Pharmacokinetic
endpoints were plasma drug concentrations over time, as
well as the area under the concentration–time curve
(AUC), half-life (
t
1/2), minimum (
C
min; trough) and
maximum (
C
max; peak) concentrations, for both
contra-ceptive steroids and antiretrovirals.
Data abstraction and management
After screening and removal of duplicates, we abstracted
relevant data from each included report using a
predesigned form. Two authors independently reviewed
selected manuscripts, with differences resolved by
consensus.
We described strengths, weaknesses, and funding source
for each included study (Tables 3 and 4) [14–65], but did
not do formal quality assessment because no formal
evidence grading system exists for pharmacokinetic
studies.
Results
Our search identified 1570 records. Fifty published
reports from 46 individual studies met the inclusion
criteria (Fig. 1, Tables 3 and 4). Four reports were
secondary analyses or subsets of the primary studies and
are included with the primary study in the tables [14–17].
The results are presented by outcome assessed, focusing
first on the most important clinical outcomes
(contra-ceptive effectiveness, antiretroviral effectiveness, toxicity
associated with combined administration), then the
pharmacokinetic data (for contraceptives and
antiretro-virals), in each case by antiretroviral class and by
contraceptive method.
Contraceptive effectiveness
Although pregnancy is the most relevant outcome, few
large studies were designed to investigate contraceptive
effectiveness. Several secondary analyses helped fill this
gap, particularly for women using nevirapine-containing
or efavirenz-containing cART. Although some small
pharmacokinetic studies of healthy women report on
pregnancy, women were generally required to use
additional contraception; these studies are included in
Table 3 but not summarized here.
Nonnucleoside reverse transcriptase inhibitors
Fourteen reports from clinical trials and six secondary
analyses described contraceptive effectiveness measures
among women using NNRTIs and hormonal
contra-ceptives (Table 3).
Oral contraceptives
Two clinical trials of women using cART and oral
contraceptives [18,19], six secondary analyses [20–25]
and five pharmacokinetic trials (mostly in healthy women
using single antiretrovirals with COCs) [26–30],
evaluated pregnancy or ovulation. No pregnancies were
found to be associated with nevirapine or efavirenz in the
prospective clinical trials.
Pregnancy rates and ovulation rates did not differ between
HIV-positive women taking COCs and
nevirapine-containing cART and those not yet taking cART [18]. In
a small trial of women using COCs with
efavirenz-containing cART, three women ovulated (out of 25) but
no pregnancies were reported [19]. Five small
pharma-cokinetic trials of NNRTIs and COCs also demonstrated
no ovulation among study participants [26–30].
In large cohort studies, pregnancy rates were slightly
higher among women taking efavirenz-containing cART
(11–15/100 woman-years) compared with women
taking oral contraceptive and nevirapine-containing
cART or
no cART (pregnancy rates 6–11/100
woman-years) [24,25]. Notably the reported pregnancy
rates in the large cohort studies are still lower than an
expected pregnancy rate of 40 per 100 woman-years
among women not using any modern contraceptive and
trying to prevent pregnancy.
Other retrospective cohort studies reported pregnancy
rates among oral contraceptive users ranging from 2.6 to
5.8 per 100 woman-years (most, but not all, women were
using nevirapine) [20,21].
Depot medroxyprogesterone acetate
Table
3
(
conti
nued
)
Referen
ce;
locat
ion
De
sign
obje
ctive
(s)
Numb
er
of
part
icipants
(
N
);
popula
tion
Interv
ention/t
reatmen
t
Resul
ts
Strength
s;
weaknesse
s;
funding
sour
ce
Kason
de
et
al
.
[51
]
Botswan
a
Seco
ndary
ana
lysis
of
RCT
To
investi
gate
the
eff
ect
of
TDF
and
the
in
teraction
of
TDF
and
hor
monal
contra
ception
on
BMD
among
HIV
-uninfe
cted
Africa
n
men
and
wom
en
One
hundred
and
fourt
een
sexu
ally
act
ive
women
at
risk
of
HIV
,
from
HIV
prev
ention
trial;
18
–
39
years;
nonpr
egnan
t
and
nonb
reast-feeding
Injecta
ble
or
impla
nt
oral
cont
racepti
ves
TDF
TDF/FT
C
place
bo
Data
not
separat
ed
fo
r
women
vs.
men
Bone
mineral
densi
ty
with
DEXA
at
distal
and
ultrad
istal
fo
rearm;
lumba
r
spi
ne;
hip
3/114
(2.6%)
had
a
low
bas
eline
bo
ne
min
eral
densi
ty;
Changes
in
bone
m
ineral
densi
ty
fo
r
women
on
eithe
r
oral
or
injecta
ble
vs.
no
cont
racepti
on
not
sig
nificant
exce
pt
fo
r
a
positi
ve
effect
of
oral
cont
racepti
ves
on
spine
bone
miner
al
densi
ty
fo
r
women
on
TDF/
FTC
Strength
s:
used
DEXA
to
measu
re
bone
mineral
densi
ty
Weakn
esses:
some
result
s
not
separ
ated
by
gen
der
or
HIV
statu
s;
no
menti
on
of
preg
nancy
or
lactati
on
or
ot
her
medica
tion
use;
few
data
on
cont
raceptive
use;
low
adheren
ce
to
TDF/FT
C;
uncl
ear
if
injec
table
group
also
includ
ed
implant
users
Funded
by
governm
ent
Luque
et
al
.
[39]
USA
Ope
n-labe
l;
mul
ticente
r;
nonrand
omized
;
ste
ady-state
pharmac
okin
etic
study
To
assess
th
e
effect
of
LPV/r
on
DMPA
ph
armacoki
netics
and
vice
versa;
and
to
asses
s
safety
and
tolera
nce
of
DMPA
giv
en
con
current
with
LPV/
r
Twenty
nonpr
egnan
t;
preme
nopa
usal
HIV
þ
women
;
on
sta
ble
LPV/r
for
at
lea
st
14
days;
no
DM
PA
withi
n
18
0
day
s
Media
n
BMI
28
DMPA cART
-conta
ining
LPV/
r
No
preg
nancies
Progest
erone
>
5
ng/ml
consi
dered
presu
mptive
ovul
ation;
zero
ovulatio
ns
note
d
No
seriou
s
adver
se
event
s;
one
grad
e
3
adv
erse
event
(pr
olonged
bleeding)
.
No
chang
es
in
CD4
þ
cell
coun
t
or
HIV
RN
A
thr
ough
we
ek
8
At
we
ek
12
–
3/24
wom
en
in
LPV/
r
grou
p
had
detec
table
HIV
RN
A;
two
due
to
antire
trovira
l
nonc
omplian
ce
Strength
s:
clearly
descr
ibed
popula
tion
and
metho
ds;
HIV
þ
women
;
assessed
ovul
ation
at
seve
ral
time
points
Weakn
esses:
smal
l
sample
size;
short
dur
ation
Funded
by
governm
ent
Todd
et
al
.
[59
]
Kenya
Seco
ndary
ana
lysis
of
PrEP
HIV
prev
ention
tria
l
To
exam
ine
PK
of
LNG
with
concur
rent
use
of
TDF-FTC
as
PrEP
Twenty
-nine
sexual
ly
active
women
at
risk
of
HIV
,
who
electe
d
to
recei
ved
LN
G
impla
nt;
ages
18
–
35
TDF/FT
C
group:
N
¼
17
Place
bo
group:
N
¼
12
Mea
n
BMI
22.6
LNG
impla
nt
TDF/FT
C
or
placebo
Follow-up
36
we
eks
No
preg
nancies
and
one
impla
nt
disco
ntinua
tion
at
7
m
onths,
with
reaso
n
for
discont
inuation
not
reco
rded
Strength
s:
TDF
levels
measur
ed
to
asses
s
for
adh
erence
Weakn
esses:
Smal
l
sample
size;
perc
entag
e
retent
ion
no
t
sta
ted
Funded
by
governm
Tab
le
3
(
conti
nued
)
Ref
erence;
locat
ion
De
sign
objecti
ve
(s)
Numb
er
of
part
icipants
(
N
);
popula
tion
Interven
tion/tr
eatmen
t
Resu
lts
Stren
gths;
we
aknesse
s;
fu
nding
sour
ce
He
ffron
et
al
.
[50]
Ken
ya,
Ug
anda
Secon
dary
analy
sis
of
PrEP
RCT
To
eval
uate
TDF/FT
C
and
TDF
efficacy
am
ong
women
using
DM
PA
com
pared
with
nonho
rmon
al
use
rs
One
th
ousand,
seven
hundr
ed
and
eighty-fi
ve
women
at
risk
of
HIV;
med
ian
age
33
years
At
enrollm
ent:
48
6
DM
PA
users
In
follow-up:
addi
tional
415
DMPA
users
TDF/FT
C,
TDF,
or
place
bo
Effi
cacy
of
PrEP
not
differen
t
for
women
usi
ng
DM
PA
com
pared
with
wo
men
using
no
hor
monal
cont
raceptio
n
Amo
ng
DMPA
use
rs:
effica
cy
64.7%
(Pr
EP
vs.
place
bo)
Amon
g
nonho
rmon
al
use
rs:
effica
cy
75.5%
(Pr
EP
vs.
place
bo)
P
intera
ction
¼
0.65
No
data
abou
t
preg
nancy
repor
ted
Stren
gths:
large
samp
le
size;
high
adheren
ce
Wea
knesses
:
second
ary
analy
sis;
self-rep
orted
cont
racepti
ve
use
;
adju
stment
for
unpro
tected
sex
but
unclear
whethe
r
or
how
cond
om
use
wa
s
collect
ed
Fun
ded
by
gov
ernme
nt
Da
y
et
al
.
[44
]
Ken
ya
Pro
spective
coho
rt
To
test
the
hypo
thesis
th
at
DMPA
wou
ld
be
associ
ated
with
in
creased
detec
tion
of
HIV-1
RN
A
in
women
initiati
ng
and
con
tinuing
cart
One
hundr
ed
and
two
HIV
þ
women
starting
cART;
med
ian
age
36;
med
ian
CD4
þ
cell
coun
t
122
cells/
m
l
At
baselin
e:
18
(18%
)
DMPA
5
(5
%)
impla
nts;
5
(5%)
oral
cont
racep
tives
cART-c
ontain
ing
ZD
V;
d4T;
3TC;
and
NVP
Seve
nty
two
com
plete
d
33
months
follow-u
p
DM
PA
did
not
increas
e
plasma
HIV
RNA
Stren
gths:
lo
ng
foll
ow-up;
adju
sted
for
ant
iretrov
iral
adheren
ce
and
CD4
þ
cel
l
count
Wea
knesses
:
self-r
eporte
d
cont
raceptive
and
antiretro
viral
use;
large
loss
to
fo
llow-u
p;
14%
chang
ed
cA
RT
regimen
;
small
numbe
r
of
women
usi
ng
DM
PA
Fun
ded
by
gov
ernme
nt
At
rio
et
al
.
[16],
Atrio
et
al
.
[56
],
Dubois
et
al
.
[17
]
US
A
Non
random
ized
clinica
l
trial
To
evaluate
the
effect
of
protease
in
hibitors
on
cervical
mucus
of
POP
users
Thirty-fiv
e
HIV
þ
women
,
age
18
–
44
years;
no
chang
es
in
m
edicati
ons;
no
re
cent
hormon
al
cont
racepti
ves;
no
immu
nocom
promise
;
no
liver
or
re
nal
diseas
e;
nor
mal
ovul
ation;
BMI
<
40;
>
30
day
s
postpar
tum
POPs
cont
aining
NE
T
In
PI
grou
p:
11
tak
ing
cART
cont
aining
ATV
(1
0/11
on
ATV
/r);
3
DRV/r;
2
LPV/r
In
cont
rol
grou
p:
four
women
not
taking
cA
RT;
13
tak
ing
com
binati
ons
includ
ing
ETR
,
RPV,
TDF,
FTC,
and
RAL
Base
line
muc
us
sco
res
simila
r
Ce
rvica
l
mucus
sco
res
in
PI
and
non-P
I
gr
oups
simi
lar
after
POP
s:
m
edian
sco
re
3.5
for
PI
group
and
four
for
control
s
score
<
10
(unfavo
rable
to
spe
rm
penet
ration)
:
81
%
of
study
group;
60
%
of
com
pariso
n
grou
p
Stren
gths:
pro
specti
ve
des
ign;
blinde
d
asses
smen
ts
Wea
knesses
:
no
bas
eline
of
periov
ulatory
m
ucus
for
all
women
;
sm
all
sample
size;
nonrand
omized
;
cART
use
sel
f-repor
ted;
result
s
no
tseparat
ed
by
antire
trovira
l
Fun
ded
by
gov
ernme
Tabl
e
3
(
continu
ed
)
Ref
erence;
locatio
n
Desig
n
objective
(s)
Num
ber
of
partic
ipan
ts
(
N
);
po
pulation
In
tervention
/treat
men
t
Resu
lts
Strengt
hs;
we
aknesse
s;
fund
ing
source
Hub
acher
et
al
.
[45]
Ken
ya
Prospe
ctive
coho
rt
To
exam
ine
ho
w
concu
rrent
use
of
ho
rmonal
cont
racep
tive
impla
nts
and
cA
RT
m
ight
les
sen
th
e
effect
ivene
ss
of
both
m
edicati
ons
Nint
y-three
sexu
ally
active
HIV
þ
nonpregn
ant
women
,age
18
–
44
years;
CD4
þ
cel
l
coun
t
200
cel
ls/
m
l;
witho
ut
recen
t
ho
rmonal
cont
raceptive
or
rifa
mpin
use,
des
ire
for
preg
nancy
,
or
cont
raindica
tions
to
impla
nt
use
LN
G
imp
lant
or
nonho
rmonal
contra
ception
NVP
-conta
ining
cart
LN
G
imp
lant
use
rs
(6
0
recruit
ed;
48
ana
lyzed
)
matche
d
to
women
not
using
ho
rmonal
contra
ception
(36
recruit
ed;
33
ana
lyzed
)
CD4
þ
cell
coun
ts
fo
r
both
groups
rose
slightl
y
but
did
not
differ
betw
een
groups
No
particip
ants
died;
six
partic
ipants
(two
imp
lant
users,
four
cont
rol
s)
diagnos
ed
with
opportu
nistic
infec
tions
Zero
preg
nanci
es
in
imp
lant
users
Strengt
hs:
large
samp
le
siz
e;
implant
insert
ed
at
study
site
Wea
knesses
:
metho
d
of
pregnan
cy
ascertai
nment
not
stated;
observa
tional
study;
no
non-cART
users;
six
wom
en
(10%
)
of
implant
group
had
imp
lant
removed
withi
n
12
mon
ths;
cART
self-rep
orted
Fund
ed
by
gov
ernme
nt
Lan
dolt
et
al
.
[15
,19]
Thai
land
Prospe
ctive;
op
en-lab
el;
no
nrandomi
zed
steady-sta
te
clini
cal
tria
l
To
asses
s
risk
of
ovulatio
n
and
saf
ety
in
women
taking
COC
s
with
cart
Fort
y-nine
HIV
þ
nonpr
egnant,
nonlact
ating
wom
en;
18
–
45
years,
with
regu
lar
men
ses,
on
EFV
-cont
aining
or
NVP
-cont
aining
cART
;
nons
mokin
g,
no
recent
injecta
ble
cont
racepti
ve
use,
no
con
traindi
cations
to
COCs
Fou
rteen
HIV
control
s
COC
contain
ing
DSG
for
two
cycles
NVP
-conta
ining
or
EFV
-contain
ing
cART
Fort
y-eight
complet
ed
study,
15
di
scontinu
ed,
includ
ing
13
due
to
protoco
ladheren
ce
issues
Ovu
lation
by
serum
progest
erone:
NVP
gr
oup:
All
women
had
progest
erone
<
1.0
ng/m
l
EFV
group:
three
women
had
progest
erone
>
3.0
ng/ml
Mo
re
women
in
EFV
group
reporte
d
adverse
even
ts
than
NVP
grou
p
Strengt
hs:
prospe
ctive
clinica
l
trial;
HIV
þ
wom
en
Wea
knesses
:
nonrand
omized
;
small
samp
le
siz
e;
sin
gle
progester
one
measu
rement;
no
adherence
in
format
ion;
high
dropout
rate
Fund
ed
by
gov
ernme
Tabl
e
3
(
conti
nued
)
Ref
erence;
locat
ion
Desig
n
objective
(s)
Number
of
partic
ipan
ts
(
N
);
populati
on
In
terventio
n/treatme
nt
Resu
lts
Stren
gths;
we
aknesse
s;
fu
nding
source
Na
nda
et
al
.
[18
]
Ug
anda,
South
Africa
Pro
spective
open
-label
no
nrandomi
zed
clinica
l
tria
l
To
com
pare
ovul
ation
and
preg
nancy
rates
betw
een
tw
o
grou
ps
of
women
:
th
ose
tak
ing
COCs
con
current
ly
with
NVP-con
taining
cART
and
those
tak
ing
COCs
alo
ne
Four
hund
red
and
two
sexual
ly
act
ive
HIV
þ
women
18
–
35
years,
with
re
gular
men
ses
and
no
cont
raindi
cations
to
COC
use;
median
age
29
and
med
ian
CD4
þ
cell
coun
t
48
6
cel
ls/
m
l
COC
-conta
ining
NG
cA
RT
group
includ
ed
women
on
NVP
-cont
aining
cA
RT;
n
¼
196
Co
ntrol
gr
oup
included
women
not
yet
eli
gible
for
cART
;
n
¼
206
O
vulation
by
serum
progest
erone
(
>
3
ng/ml
)
cA
RT
gr
oup:
43/1
68
(26%
)
ovul
ated
in
cycle
1;
30/
163
(18%
)
in
cycle
2;
18/
163
(11%)
in
both
cycles
No
n-cART
gr
oup:
26/1
68
(15%)
ovulate
d
in
cycl
e
1;
31/165
(19%)
in
cycl
e
2;
and
20/165
(12%
)
in
both
cycles
No
signific
ant
differ
ence
in
ovul
ation
rates
between
groups
Preg
nancy
rates
(per
100
woman
-years):
10.
in
cART
group
and
10
.1
in
non-cAR
T
group
Ad
verse
event
s
simila
r;
five
seriou
s
adverse
event
s,
all
in
non-cA
RT
grou
p
Stren
gths:
prospe
ctive
clinica
l
trial;
COCs
and
ant
iretrov
irals
at
steady
state;
m
ultiple
progest
erone
measu
remen
ts;
large
samp
le
size;
HIV
þ
women
;
inform
ation
on
COC
adheren
ce
Wea
knesses
:
nonran
domized
,
self-reporte
d
cART
and
COC
adheren
ce;
no
ph
armaco
kinetic
measur
es
Fund
ed
by
gov
ernme
nt
Crau
wels
et
al
.
[27
]
UK
Ope
n-labe
l,
three
peri
od
ph
armacoki
netic
study
To
eval
uate
the
effect
of
RP
V
on
COC
phar
macoki
netics
and
vice
versa,
and
asses
s
eff
ects
on
sex
ho
rmones
and
safety
of
co-adm
inistr
ation
Eighteen
healthy
nons
mokin
g
wo
men,
18
–
45
years;
BMI
18
–
30
(medi
an
24
.6);
67%
white;
exclu
ded
preg
nant,
brea
st-feed
ing,
or
men
opausal
women
,
those
with
history
of
drug/
alcoh
ol
abuse,
skin
diseas
e,
or
any
sig
nificant
med
ical
problem
s;
use
of
conco
mitant
med
ication
COC
-conta
ining
NET
In
third
cycle;
RPV
25
m
g
daily
days
1
–
15
Th
irteen
compl
eted
trial
Pro
gestero
ne;
LH
;
and
FSH
on
day
1
and
14;
0
ovul
ations;
no
effect
on
FSH;
LH
No
differen
ce
in
adver
se
event
s
Stren
gths:
cle
arly
described
popula
tion
and
metho
ds;
dir
ectly
observe
d
therap
y
Wea
knesses
:
healt
hy
women
;
short-t
erm
dosin
g;
singl
e
antire
trovira
l;
high
discont
inuation
rate
Fund
ed
by
in
Tabl
e
3
(
continued
)
Refer
ence;
location
Desig
n
ob
jective
(s)
Numb
er
of
partic
ipants
(
N
);
popu
lation
Interv
ention
/treat
ment
Resul
ts
Strengt
hs;
weakn
esses
;
fundin
g
source
Polis
et
al
.
[46]
Ugan
da
Retrosp
ective
coh
ort
To
asses
s
the
effect
of
injec
table
con
traceptiv
e
use
on
cA
RT
effect
ivene
ss
and
adh
erence
to
cart
Four
hundred
and
eig
hteen
pregnant
and
nonpregn
ant
sexual
ly
active
HIV
þ
wom
en
initiati
ng
cA
RT,
witho
ut
tuberc
ulosis,
with
informat
ion
on
bas
eline
viral
load
51/4
18
(12%
)
use
d
unspeci
fied
injec
tables
at
baselin
e
cA
RT
(not
specified
)
Failu
re
defin
ed
as
failu
re
to
ach
ieve
viro
logic
sup
pressio
n
at
12
month
s,
sw
itch
to
second
-line
th
erapy,
or
death
withi
n
12
months
of
cART
in
itiation
No
diff
erence
in
treatmen
t
fai
lure
at
12
month
s
bet
ween
injecta
ble
users
and
nonusers
(11
vs.
12
%)
Injec
tables
no
t
asso
ciated
wi
th
cART
failure
in
sen
sitiv
ity
analy
sis
re
stricted
to
women
wi
th
com
plete
infor
mation
wh
o
nev
er
use
d
pi
lls
or
imp
lants
No
diff
erences
in
cART
adh
erence
at
6
and
12
m
onths
for
injecta
ble
use
rs
and
nonusers
Strengt
hs:
large
sample
siz
e
Wea
knesses
:
retrospe
ctive;
ob
servati
onal
database
ana
lysis;
sel
f-rep
orted
contra
ceptive
use
;
in
consiste
nt
injec
table
use
over
ti
me;
type
of
injecta
ble
and
cA
RT
no
t
spe
cified
Fund
ed
by
gov
ernment
Carten
et
al
.
[52
]
USA
Open-l
abel
two
period
phar
macoki
netic
stu
dy
To
determ
ine
the
effect
of
EFV
on
the
ph
armaco
kinetic
s
of
LN
G
EC
and
vice
ver
sa,
and
asses
s
safety
Twen
ty-four
healthy
women;
18
–
45;
norm
al
BMI
(mea
n
BMI
27)
with
no
recent
use
of
hormon
al
contra
ceptives
or
othe
r
interacti
ng
med
ication
s;
women
were
eithe
r
sterilize
d
or
used
two
nonho
rmonal
contra
ceptive
metho
ds
LN
G
ECPs
(0.75
mg)
at
0
and
12
h
on
day
s
0
and
17
EFV
600
m
g
72
h
after
day
0,
for
14
days
Twen
ty-one
women
com
plete
d
study
Follow
-up
preg
nancy
test
at
vis
it
3
(study
day
not
spe
cified
)
Preg
nancy
test
result
s
not
giv
en
No
grad
e
3
or
4
treatmen
t-re
lated
to
xicitie
s.
Strengt
hs:
clear
ly
des
cribed
po
pulation
and
metho
ds
Wea
knesses
:
small
samp
le
siz
e;
hea
lthy
women;
singl
e
antire
tro
viral;
ovulatio
n
not
tes
ted;
single
fo
llow-u
p
preg
nancy
tes
t
bu
t
tim
ing
and
re
sults
no
t
giv
en
Fund
ed
by
indust
ry
Pisci
telli
et
al
.
[29
]
UK
Randomi
zed
crossov
er
phar
macoki
netic
stu
dy
To
exam
ine
if
GSK224
8761
(fosdev
irine)
intera
cts
with
CY
P450
subst
rates,
includ
ing
COC
s
Ten
hea
lthy
women
,
without
hepatit
is
and
not
taking
any
med
ications
COC
containi
ng
DRSP
GS
K228761
200
mg
or
placebo
days
1
–
11
No
diff
erences
in
LH/FSH
No
seriou
s
adv
erse
event
s
or
treat
ment
due
to
adverse
even
ts,
and
no
signific
ant
lab
oratory
abno
rmalities
Strengt
hs:
random
ize
d
Wea
knesses
:
short
term
adm
inistr
ation;
healthy
women
;
sin
gle
antire
trovira
l;
sm
all
samp
le
size;
very
few
study
detai
ls
provided
;
trials
of
fo
sdevirine
on
hold
due
to
othe
r
saf
ety
con
cerns;
study
termi
nated
early
fo
r
unkn
own
re
asons
Fund
ed
by
indust
Table
3
(
cont
inued
)
Referen
ce;
lo
cation
De
sign
obje
ctive
(s)
Numb
er
of
part
icipant
s
(
N
);
popula
tion
Interv
ention
/treatm
ent
Resul
ts
Strength
s;
weakn
esses;
funding
sou
rce
Schw
artz
et
al
.
[21]
South
Afr
ica
Pro
spective
coh
ort
To
determi
ne
the
inciden
ce
of
unplan
ned
preg
nancies
in
HIV
þ
women
on
cART
;
to
asses
s
contra
ceptive
use
and
asso
ciations
wi
th
unplan
ned
preg
nancy
Eight
hundred
and
fifty
HIV
þ
women
;
ages
18
–
35
;
on
/startin
g
cART
;
not
preg
nant
,
re
cently
preg
nant
,
or
breast-fee
ding;
no
known
in
fertility
243
(29%
)
using
HC:
Injec
tables
(DMPA
þ
NE
T-EN;
192)
;COCs
(46);
imp
lants
(t
ype
not
sta
ted
4);
IUD
(1)
Mult
iple
antire
tro
virals:
52%
NVP-con
taining
regim
ens
;
42
%
EFV-cont
aining
One
hundred
and
seve
nty
preg
nanci
es
in
161
women
;
105
(62%)
unpl
anned
(i
ncidenc
e
rate:
16.1/10
0
woman-years
Nine
of
105
unplan
ned
preg
nanci
es
were
pote
ntiall
y
hormon
al
cont
racep
tive
failures;
seve
n
on
NVP
and
on
e
on
EFV
;
incid
ence
of
unpl
anned
pregnan
cy
4.4
per
100
woman
-years
One
failure
not
related
to
adher
ence
in
COC
user
(5.8
/100
woman
-years)
Seven
injec
table
failures
(two
DM
PA;
five
NET-EN;
(incid
ence
rate
4.
2/100
woman
-years)
;
5/7
in
last
2
weeks
of
injection
cycle
Strength
s:
preg
nancy
by
urine
hCG;
cA
RT
confi
rmed
by
pharmac
y
reco
rds;
con
traceptiv
e
failures
confi
rmed
throu
gh
re
cords
revie
w
Weakn
esses
:
ob
servati
onal
study;
cont
racepti
ve
use
sel
f-report
ed;
repo
rted
only
at
bas
eline;
did
not
repo
rt
which
HC
failur
es
were
using
whic
h
antire
tro
viral
Funded
by
governm
ent
Kreitchm
ann
et
al
.
[33
]
Brazil
Pro
spective
coh
ort
To
evalu
ate
the
safety
and
effica
cy
of
ENG
impla
nts
amo
ng
HIV
þ
women
Seve
nty
nine
HIV
þ
wom
en
with
comorb
iditie
s
and
po
or
adherence
to
other
cont
racep
tive
metho
ds;
m
ean
age
29;
mean
we
ight
59
kg
(ran
ge
42
–
10
4)
ENG
impla
nt
At
bas
eline:
47
use
d
cART;
nine
beg
an
cA
RT
dur
ing
foll
ow-up
(P
I
cont
aining-regim
en
31;
NNR
TI-cont
aining
25
)
Women
followed
up
every
6
mon
ths
over
3
years
and
0
preg
nanci
es
noted
Four
wom
en
had
elevated
liver
enzymes
:
all
coin
fected
with
hepat
itis
C
ENG
impla
nt
remov
ed
in
five
women
:
two
had
tuba
l
ligation;
one
hys
terectom
y;
two
bec
ause
of
excessi
ve
bleed
ing
Menst
rual
irregu
larity
most
com
mon
adv
erse
event
;
two
unrela
ted
deaths:
one
of
AIDS,
and
one
of
card
iac
ar
rest
(baseli
ne
card
iomyo
path
y)
Strength
s:
verified
contra
ceptive
use
;
pro
spective
stu
dy;
HIV
þ
women
Weakn
esses
:
sel
f-report
ed
preg
nancy
;
did
no
t
spe
cify
cART
type
Fundin
g
source
not
spe
Tab
le
3
(
conti
nued
)
Ref
eren
ce;
locat
ion
De
sign
objecti
ve
(s)
Numb
er
of
part
icipants
(
N
);
popula
tion
Interven
tion/tr
eatmen
t
Results
Stren
gths;
weaknesse
s;
fu
nding
sour
ce
Jo
hnson
et
al
.
[47
]
US
A
Retr
ospecti
ve
coho
rt
To
examin
e
how
use
of
hormonal
cont
racepti
ves
affects
respo
nse
to
cA
RT
One
hu
ndred
and
seve
n
HIV
þ
adolesce
nt
wo
men
re
por
ti
ng
consi
stent
cA
RT;
median
age
1
7
year
s
Seventy-two
perc
ent
oral
cont
raceptive
s
Twenty
eig
ht
percent
DMPA
cART
regim
ens
includ
ed
ZDV
and
ZD
V/3TC
No
differen
ce
in
CD4
þ
cell
coun
ts
ove
r
tim
e
Viral
load
dec
reased
over
time
in
hormon
al
use
rs
and
nonu
sers;
bu
t
an
intera
ction
wa
s
noted:
decr
ease
in
viral
load
wa
s
sligh
tly
slower
(1.2
10
3;
95
%
CI:
6.2
10
5
to
2.4
10
3 cop
ies/ml
log
viral
load
per
day
;
P
¼
0.
03)
among
horm
onal
con
traceptiv
e
users
Stren
gths:
HIV
þ
women
Wea
kne
sses:
retro
spective
;
chang
es
in
viral
load
of
quest
ionable
cli
nical
signific
ance;
cont
racepti
ve
use
self-rep
orted;
not
sep
arate
typ
e
of
cont
raceptive
s
Fun
ded
by
governm
ent
Stu
art
et
al
.
[30]
Mal
awi
Pro
spective
nonran
domiz
ed
clinica
l
tria
l
To
assess
th
e
feasibi
lity
of
measurin
g
anovu
lation
in
a
pharmac
okin
etic
study
of
COCs
and
antire
tro
virals
Nine
wom
en
ages
21
–
35
(3/
group)
with
simila
r
age
and
BMI
:
gr
oup
1
includ
ed
HIV
þ
wom
en
on
cA
RT;
group
2
includ
ed
HIV
þ
wom
en
not
on
cA
RT;
and
group
3
includ
ed
HIV
wom
en
COC
with
NG
NVP-containi
ng
cART
or
no
cART
Ovulation
by
serum
progest
erone
(
>
3.0
ng/
ml)
on
day
14
;
0
ovul
ations
Stren
gths:
Clearly
des
cribed
popula
tion
and
methods
;
valid
assay
s;
includ
ed
HIV
þ
wo
men
Wea
kne
sses:
very
smal
l
sample
size;
nonran
domized
;
progest
erone
measu
red
only
once
Fun
ding
sou
rce
not
reporte
d
Sevi
nsky
et
al
.
[26]
US
A
Ope
n-labe
l
3-p
eriod
pharmac
okin
etic
study
To
examin
e
effect
of
EFV
on
pharmac
okin
etics
of
EE
and
NGMN
and
vic
e
versa
Twenty
-eight
healthy
women
;
18
–
45
years
(medi
an
26);
BMI
20
–
32
(medi
an
25);
on
COC
s
for
at
least
2
months
and
no
bas
eline
saf
ety
issues
or
brea
kthrough
bleed
ing
COC-co
ntaini
ng
NGM
EFV
600
m
g
daily
fo
r
14
days
during
third
cycle
Ninete
en
wom
en
com
pleted
study
Pregnancy
tes
t
day
108;
result
s
not
repor
ted
Progester
one
levels
simila
r
and
all
<
1.
25
ng/m
l
No
discont
inuation
s
for
adver
se
events;
thr
ee
seve
re
adver
se
event
s:
heada
che;
anhed
onia;
and
depr
ession;
one
seriou
s
adver
se
event
–
suici
de
attemp
t
after
treatmen
t
in
a
woman
with
pri
or
undiscl
osed
depress
ion
Stren
gths:
clearly
describ
ed
popula
tion
and
methods
Wea
kne
sses:
smal
l
samp
le
size;
single
progester
one
measur
ement
per
cycle;
preg
nancy
testing
result
s
not
repor
ted;
healt
hy
women
;
singl
e
antire
trovira
l;
high
disco
ntinuati
on
rate
Fun
ded
by
