Group Research Article

1. See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/229081926
Vaginal Ring Adherence in Sub-Saharan Africa: Expulsion, Removal, and
Perfect Use
Article in AIDS and Behavior · July 2012
DOI: 10.1007/s10461-012-0248-4 · Source: PubMed
CITATIONS
58
READS
120
12 authors, including:
Some of the authors of this publication are also working on these related projects:
VOICE-D (MTN-003D): An Exploratory Study of Potential Sources of Efficacy Dilution in the VOICE Trial View project
Anti-HIV Microbicide View project
Ariane van der Straten
RTI International
167 PUBLICATIONS 6,103 CITATIONS
SEE PROFILE
Katherine Young
8 PUBLICATIONS 290 CITATIONS
SEE PROFILE
Joseph Romano
NWJ Group LLC
36 PUBLICATIONS 1,465 CITATIONS
SEE PROFILE
Annalene Nel
International Partnership for Microbicides
55 PUBLICATIONS 1,408 CITATIONS
SEE PROFILE
All content following this page was uploaded by Cynthia Woodsong on 15 April 2016.
The user has requested enhancement of the downloaded file.

2. ORIGINAL PAPER
Vaginal Ring Adherence in Sub-Saharan Africa: Expulsion,
Removal, and Perfect Use
Elizabeth T. Montgomery • A. van der Straten • H. Cheng • L. Wegner •
G. Masenga • C. von Mollendorf • L. Bekker • S. Ganesh • K. Young •
J. Romano • Muungo. A.T.Lungwani Nel • C. Woodsong
Published online: 13 July 2012
Ó Springer Science+Business Media, LLC 2012
Abstract In sub-Saharan Africa, HIV incidence and
prevalence remain disproportionately high among women.
Vaginal rings (VRs) have been formulated for the delivery
of antiretroviral-based microbicides, and their favorable
safety and tolerability profiles reported in clinical studies.
Although the concept of drug release through a VR has
existed since 1970, and VRs have been marketed since
1992 for contraceptive or hormone replacement purposes,
VR use as a microbicide delivery system is a novel
application. This is the first study to evaluate VR adherence
among African women in the context of its potential use as
an HIV prevention method, to examine predictors of
adherence, and to describe clinical or contextual reasons
for VR removals or nonadherence. This was a randomized
trial of the safety and acceptability of a placebo VR worn
for 12 weeks in 170 HIV-negative, African women aged
18–35 in four clinic sites in South Africa and Tanzania.
The findings suggest that adherence to VR use in the
context of HIV prevention trials in these communities
should be high, thereby enabling more accurate assessment
of an active microbicide safety and efficacy.
Keywords Vaginal ring Á Adherence Á Sub-Saharan
Africa Á Female-controlled HIV prevention methods Á
Microbicide delivery
Introduction
In sub-Saharan Africa, HIV incidence and prevalence
remain staggeringly and disproportionately high among
women [1]. To address women’s heightened vulnerability
to HIV, the development of female-initiated methods for
HIV prevention, including microbicide gels, barriers
(female condoms, cervical barriers) and vaginal rings
(VR), remains a critical research priority.
While the concept of drug release through a VR has
existed since 1970, and VRs have been marketed since
1992 for contraceptive or hormone replacement purposes
[2], investigation of VR use as a microbicide delivery
system is relatively new. VRs have been formulated to be
worn continuously for 28-days during which antiretroviral-
based microbicide(s) are slowly released. Thus far the
favorable safety and tolerability profile of VRs containing
E. T. Montgomery (&) Á A. van der Straten Á H. Cheng Á
L. Wegner
Women’s Global Health Imperative, RTI International
(Research Triangle Institute), 114 Sansome Street, Suite 500,
San Francisco, CA 94104-3812, USA
e-mail: emontgomery@rti.org
A. van der Straten
Center for AIDS Prevention Studies, Department of Medicine,
University of California San Francisco, San Francisco, CA, USA
G. Masenga
Kiliminjaro Christian Medical Center, Moshi, Tanzania
C. von Mollendorf
Wits Reproductive Health and HIV Research Institute,
Johannesburg, South Africa
L. Bekker
University of Cape Town and Desmond Tutu HIV Foundation,
Cape Town, South Africa
S. Ganesh
South African Medical Research Council, Durban, South Africa
K. Young Á A. Nel Á C. Woodsong
International Partnership for Microbicides, Paarl, South Africa
J. Romano
NWJ Group, LLC, Wayne, PA, USA
123
AIDS Behav (2012) 16:1787–1798
DOI 10.1007/s10461-012-0248-4

3. dapivirine, a non-nucleoside reverse transcriptase inhibitor,
have been reported in clinical studies conducted in the US
and Europe [3, 4]. Importantly, VR use for any purpose has
been nonexistent in sub-Saharan Africa. Consequently, it is
important to consider the social and contextual determi-
nants surrounding use of this investigational HIV preven-
tion method.
In contrast to many other HIV prevention technologies
being tested, the VR requires minimal action on the part of
the user to achieve product adherence. This may turn out to
be an important advantage of a VR, as it may be inserted
and worn continuously for 28 days (or potentially longer),
and it does not require daily, intermittent, or coitally
associated application of an active ingredient. As a result,
product adherence, both within and outside of a clinical
trial context, may be easier to achieve. Adherence to
product use is critical for accurate estimation of safety and
efficacy in clinical trials, and for maximum protection by
an efficacious product. This was well demonstrated by the
recently published and promising results of the CAPRISA
004 and iPrEX trials. Both trials reported overall effec-
tiveness, as well as dose-response relationships, between
the effect of the intervention and adherence level in sub-
group analyses [5, 6]. Indeed, lower-than-anticipated
adherence to product has been a major challenge, and is
believed to have contributed to ‘‘efficacy dilution’’ in
several randomized controlled trials of female-initiated
HIV prevention products [7, 8]. Although analyses are still
ongoing, suboptimal adherence was a key reason for the
early closure of the Fem PrEP study of oral Truvada and is
likely to be a main factor for early closure of the oral and
vaginal tenofovir arms of the Microbicide Trials Network’s
VOICE study [9–13] Consequently, the identification of
new and effective technologies or strategies that can
increase adherence, thereby narrowing the ‘‘efficacy-
effectiveness gap’’, is an urgent priority.
Limited evidence exists about adherence to the use of
VRs for any indication, especially in developing countries.
A study in Brazil compared user preferences for three
potential microbicide delivery systems (applicator, VR,
diaphragm) using a crossover design among 405 couples.
Although the study reported that 89 % of women had
perfect VR adherence for the 28 days of use, the study used
the NuvaRingÒ contraceptive VR because a placebo was
unavailable; therefore, use of an active contraceptive
product may have influenced adherence behavior [14].
Additionally, in two large NuvaRingÒ efficacy trials in the
United States and Europe, participants were told they could
remove the VR for sexual intercourse, and reinsert it within
3 h of removal. Despite this instruction, more than 60 % of
women reported that they never removed the VR during ten
consecutive months and 86 % of the monthly use cycles
among the intent-to-treat population (n = 2,322) were
considered compliant with the dosing regimen [15, 16].
Further, after 3 months of use, the majority of this study
population (81 %) reported a preference for the ring
compared to oral contraceptives, primarily because they
did not need to remember to take something daily and it
was easy to use [15]. A similar proportion (57 %) of
American students, randomly assigned to VR use for
3 months, was classified as ‘‘perfect users’’ for the entire
study period [17]. Finally, while the multinational
NuvaRingÒ study reported that 30 % of male partners
could detect the ring during sex and they generally did not
mind its use [15], there are limited data about male partner
reaction to VR use.
To inform the development of clinical trials of antiret-
roviral-based microbicide VRs, the International Partner-
ship for Microbicides (IPM) 011 trial was conducted to
investigate the safety and acceptability of a placebo VR
worn continuously for three consecutive 4-week intervals,
in an African setting [18]. This is the first study to evaluate
VR adherence among African women in the context of its
use as an investigational HIV prevention method. Here we
also examined predictors of adherence, described clinical
or contextual reasons for involuntary and voluntary remo-
vals of VR, and nonadherence. Favorable safety results
have been reported elsewhere, and detailed acceptability
findings are presented simultaneous to this study in a
companion publication [19].
Methods
Study Design and Procedures
The IPM 011 study was a randomized trial of the safety and
acceptability of a placebo VR worn for 12 weeks in 170
HIV-negative, African women aged 18–35 [20]. The trial
was conducted from April 2007 to March 2010 in four
clinic sites in two countries: Durban, Johannesburg, and
Cape Town, South Africa; and Moshi, Tanzania. Women
were randomized in a crossover design to wear the VR for
12 weeks, followed by a 12-week period of nonuse for
observational safety (Group A), or the reverse-order regi-
men (Group B). At enrollment or the crossover visit,
depending on group assignment, participants were taught
how to insert and remove the VR using a translucent pelvic
model. Participants were provided with an illustrated,
African-language instruction sheet and dispensed with a
VR. Participants then inserted their rings at the research
centre. A staff member checked to ensure proper placement
for all women, and provided assistance with insertion if
needed.
The study VR was an off-white, flexible, tin-catalyzed,
silicone elastomer matrix ring that was 56 mm in outer
1788 AIDS Behav (2012) 16:1787–1798
123

4. diameter, 7.7 mm thick, and contained no active agents. As
a comparison, NuvaRing is similarly flexible and 54 mm in
outer diameter, but is clear, only 4 mm thick, and is made
of a different material (ethylene co-vinyl acetate). Ring
instructions specified that the ring was to be worn contin-
uously and not to be removed until the next monthly visit.
Participants were advised to refrain from insertion of
vaginal products (e.g., tampons, products to enhance sex or
clean the vagina). If the ring was expulsed, participants
were instructed to rinse the ring with lukewarm water, and
to re-insert it or to come to the clinic for a replacement VR
if it could not be retrieved.
Following enrollment, participants were seen at least
monthly during the study period. At each follow-up visit, a
clinical examination was conducted. During the 12-week
period of VR use, a face-to-face behavioral questionnaire
was administered to participants at each visit (Week 2, 4, 8
and 12). Questions included whether the VR was ever out
of their vagina, and if applicable, the frequency, duration,
reasons and circumstances surrounding each removal or
expulsion. At follow-up visits women removed the VR,
washed it, and reinserted it under direct observation.
Although clinicians were prepared to assist women to
remove and reinsert the VRs after three failed attempts, this
assistance was not needed. Participants with abnormal
vaginal findings during follow-up visits were temporarily
suspended from VR use.
Prior to study exit, participants were asked whether they
would like to be contacted for further participation in a
focus group discussion (FGD), and whether they granted
permission for study staff to contact their male partners for
an in-depth interview (IDI). Male partners were contacted
for participation only if their female partner had granted
permission. Using convenience sampling, FGD participants
were contacted by study staff using different recruitment
approaches. In Moshi, for example, participants were
invited from among those exiting the trial closest to the
time of the scheduled FGD. In Johannesburg, participants
were recruited sequentially from a list of exited participants
until the target number of participants was reached.
Qualitative data were captured through six FGDs with
48 exited female study participants and 19 IDIs with male
partners of exited study participants from October 2007 to
December 2009: two FGDs were conducted at each of the
Johannesburg and Moshi sites and one FGD was conducted
at each of the Cape Town and Durban sites. The number of
participants in each FGD ranged from 5 to 11 participants
(mean 8, median 8). From October 2007 to March 2009, 9
male partners were interviewed in Johannesburg, and 10
male partners were interviewed in Moshi. Because of
resource constraints, and reported lack of partner willing-
ness or interest to participate, no male partners were
interviewed at the other sites.
The FGDs and IDIs were led by same gender trained
facilitators, attended by note-takers and conducted in the
local language.
Measures and Analysis
Of the 170 women enrolled in the study, 12 were not dis-
pensed with a ring, and 1 woman received a ring but had no
follow-up data. Eleven of the women not receiving a ring
were discontinued prior to the ring use regimen for being
classified as lost to follow up (n = 5); missing or being late
to visits (n = 4); inappropriate enrollment (n = 1); or
persistent menses (n = 1). The 12th woman withdrew
consent. As such, the analytic sample for this analysis is
comprised of 157 women. Baseline demographic and sex-
ual behavior characteristics of the participants were sum-
marized for the overall analytic sample, and for individuals
who did (n = 59) and did not (n = 98) participate in the
qualitative data collection activities. Women were classi-
fied as participating in the qualitative component if they
only participated in an FGD (n = 40), if only their male
partner participated in an IDI (n = 11), or if both women
and their partner were involved (n = 8). Although the
qualitative data portion of the study was not designed to be
fully representative, v2
statistics were computed to evaluate
any significant differences between individuals participat-
ing in the qualitative component versus those who did not.
At each follow-up visit, participants were asked to self-
report if the VR ever came out of their vagina since their last
clinic visit. Women who responded affirmatively were asked
whether the ring was removed (voluntarily) or expelled
(involuntarily) and the reason(s) for this, the number of
times the VR came out, the number of days the VR was not
worn in the past 7 days and since her last visit, and what
activity she was engaged in when the VR came out.
Two quantitative measures of adherence, perfect
adherence and monthly adherence, were tabulated and
evaluated by study group (A or B) to rule out an order
effect. ‘‘Perfect adherence’’ was measured through
dichotomous response to the question: ‘‘Did the vaginal
ring ever come out of your vagina? (yes/no).’’ Responses
across all three visits were summed, and women without
three measurements (because of missed follow-up visits or
missing data) were excluded. Women who reported that the
VR never came out for the entire 3-month period they were
meant to wear it were classified as ‘‘perfect adherers.’’
Monthly adherence was assessed by computing the pro-
portion of whole or partial days (more than 12 h) that
participants wore the VR in each visit interval. Participants
were classified as ‘‘80 % adherent’’ if the VR was in the
vagina for 80 % or more days (or partial days) since the
previous visit, per self-report. They were classified as
‘‘100 % adherent’’ if the VR never came out, or was in the
AIDS Behav (2012) 16:1787–1798 1789
123

5. vagina for 100 % of the days (or partial days), since the
previous visit.
Predictors of perfect adherence were modeled by exam-
ining baseline demographic and behavioral variables (e.g.,
marital status, site, ever used male condoms), and follow-up
attitudinal and behavioral variables assessed after 12 weeks
of VR use (e.g., condom use during study, concerned about
VR being lost or coming out). Predictors of monthly adher-
ence were modeled by examining the same variables from
each follow-up visit interval. v2
frequencies were used to
examine unadjusted odds ratios, 95 % confidence intervals
(CIs), and p values for the bivariate association between
predictors of interest and perfect adherence and monthly
adherence (as defined above), respectively. Predictors sig-
nificant at the p 0.20 level were retained for consideration
in a multivariate logistic regression model where adjusted
odds ratios (AORs) and associated significance levels and CIs
were computed.
Qualitative analysis was guided by a conceptual
framework that holistically examined adherence to the VR
by considering three aspects of product use: (1) product
attributes; (2) the influence of relationship attributes; and
(3) attributes of the sexual encounter [21]. This framework,
which is also reflected in the structure of the question-
naires, was designed to be flexible and has been used in
previous research of microbicides and the diaphragm. It
was easily adapted to the VR context [22–24].
For analysis, interviews were audiotaped and transcribed
into English. Using an inductive approach, the analysis team
identified the themes and categories most relevant to the
objectives of this study. Through an iterative process, the
team developed a codebook that guided the analysis of
transcripts. Inter-coder reliability was established by all five
members of the analytic team coding the first four transcripts
blinded, followed by a series of iterative consensus coding
meetings. Once the team was satisfied that coders were
applying codes consistently, the remaining transcripts were
singly-coded by two members of the analytic team using the
NVivo qualitative software package (version 8.0, QSR
International), while a third member reviewed the coded
transcript for consistency. A team of qualitative analysts
then reviewed and summarized findings from product use
and adherence-related codes, created memos and a final
analysis report through an iterative process that involved
regular meeting and discussions among the team members.
Results
Study Sample
The baseline characteristics of the analytic sample
(n = 157) are presented in Table 1. The majority of the
study sample was Black African (94 %), the median age
was 27 (range 18–35 years), and the majority (70 %) were
unmarried. Eighty-seven were in group A and received and
used the ring for the first 12 weeks, followed by 12 weeks
of non-use; 70 were in group B and had the reverse order
regimen. Almost all of the participants (98 %) reported
having a main sex partner; 28 % reported having only one
sex partner in the past 3 months. Only 12 % of women in
this study perceived their risk of getting HIV as higher than
others in their community. About 18 % of the study sample
reported having never used a male condom, and the
majority of these participants were from the Moshi,
Tanzania, study site (data not shown). This pattern was also
observed in the report of condom use in the past 7 days. A
substantial proportion (46 %) of women had participated in
previous microbicide research. Use of vaginal products in
the past 3 months was reported by 30 % of participants
overall. Most participants (78 %) disclosed study partici-
pation to their primary male partner prior to VR use.
The characteristics of the women who participated in the
qualitative component, or whose male partner did so, were
comparable with women who did not participate. However,
samples differed significantly in regard to race (no non-
Black African women participated in the qualitative com-
ponent), condom use, and site participation. These differ-
ences are driven by the fact that the Moshi site in Tanzania
provided the majority of the qualitative data (44 %). All of
these women were Black African and they were less likely
to have ever or recently used male condoms (data not
shown).
Self-Reported Adherence
During the 12-week periods of VR use, adherence to study
product was high in both study groups: 147 (93 %) women
had data available from all three VR regimen visits, and of
these, 120 (82 %) reported no VR removals and were
considered to be ‘‘perfectly adherent’’ users (Table 2).
Reported monthly adherence levels were even higher: at
each visit interval, 94–100 % of participants reported
wearing the VR for 100 % of the days since their last visit
(Table 2). Across study groups and visit, almost all (99 %)
participants reported wearing the VR for at least 80 % of
the days they were meant to. Of note, the proportion of
days the VR was worn may have included days where the
VR was out of the vagina for part of the day, provided that
time period lasted 12 h or less. After 12 consecutive hours,
the VR was classified as having been out for one ‘‘day’’.
Only a small proportion of women at each visit (3 %,
Table 2) reported VR removals or expulsions resulting in
the ring out for 1 day or longer ([12 consecutive hours).
The qualitative data findings support the high levels of
adherence to the VR described in the quantitative data.
1790 AIDS Behav (2012) 16:1787–1798
123

6. Table 1 Baseline characteristics of participants enrolled, received study product, and participated in qualitative data collection
Characteristic Analytic sample
(n = 157)
In qualitative
component (n = 59)a
Not in qualitative
component (n = 98)
p valued
n % n %
Ageb
27 (range 18–35) 29 (range 19–34) 26 (range 18–35) 0.02
Race
Black 148 94.3 59 100.00 89 90.8
Indian/cape colored 9 5.7 0 0.00 9 9.2 0.01
Marital status
Married 47 29.9 18 30.5 29 29.6
Unmarried/divorced/separated/widowed 110 70.1 41 69.5 69 70.4 1.00
Has main sex partner
Yes 154 98.1 58 98.3 96 98.0
No 3 1.9 1 1.7 2 2.0 1.00
Number of sex partners in past 3 months
1 43 27.6 15 25.4 28 28.9
2? 113 72.4 44 74.6 69 71.1 0.71
Perceived risk of HIV compared to others
High 19 12.3 11 18.6 8 8.3
Same or lower than others 136 87.7 48 81.4 88 91.7 0.08
Ever used male condom
Yes 128 81.5 43 72.9 85 86.7
No 29 18.5 16 27.1 13 13.3 0.04
Condom use in past 7 days with main partnerc
Every time 82 64.1 26 53.1 56 70.9
Not every time 46 35.9 23 46.9 23 29.1 0.06
Previously participated in microbicide study
Yes 72 45.9 23 39.0 49 50.0
No 85 54.1 36 61.0 49 50.0 0.19
Use of vaginal products
For cleaning 21 13.4 10 17.0 11 11.2 0.34
For menstruation 19 12.1 11 18.6 8 8.2 0.08
For sex: to make vagina dryer, wetter,
tighter or nicer smelling
8 5.1 3 5.1 5 5.1 1.00
For healing or treating 14 8.9 7 11.9 7 7.1 0.39
For pregnancy prevention 4 2.6 1 1.7 3 3.1 1.00
For any of the above purposes 47 30.0 23 39.0 24 24.5 0.07
Site
Moshi 48 30.6 26 44.1 22 22.5
Johannesburg 48 30.6 21 35.6 27 27.6
Durban 44 28.0 7 11.9 37 37.8
Cape Town 17 10.8 5 8.5 12 12.2 0.01
Study group
A (VR ? no VR) 87 55.4 39 66.1 48 49.0
B (no VR ? VR) 70 44.6 20 33.9 50 51.0 0.05
Partner knew about study
Prior to start of ring use 123 78.3 51 86.4 72 73.5
After ring use initiated or never 34 21.7 8 13.6 26 26.5 0.07
VR vaginal ring
a
Includes data describing 48 women who participated in focus group discussions (FGDs) and 11 female partners of men who participated in in-depth interviews
(IDIs). Eight (8) women in FGDs had male partners who participated in IDIs. Consequently, qualitative interviews were conducted with 67 individuals, represented
by 59 female study participants
b
Median values (and range) are reported for this variable, Wilcoxon rank-sum test used to compare groups
c
Among those reporting sex in the past 7 days
d
P values associated with Fisher’s exact test
AIDS Behav (2012) 16:1787–1798 1791
123

7. Table 2 Self –reported vaginal ring adherence and removals, by group and visit
Week 4 FU visita
(n = 154)
Week 8 FU visita
(n = 155)
Week 12 FU visita
(n = 149)
Group A
n (%)
Group B
n (%)
Total
n (%)
Group A
n (%)
Group B
n (%)
Total
n (%)
Group A
n (%)
Group B
n (%)
Total
n (%)
VR never removed: ‘‘perfectly adherent’’b
60 (75) 60 (90) 120 (82)
VR in vagina 100 % or more of days 80 (95) 69 (100) 149 (97) 80 (95) 69 (99) 149 (97) 77 (94) 67 (100) 144 (97)
VR in vagina 80 % or more of days 83 (99) 69 (100) 152 (99) 83 (99) 70 (100) 153 (99) 80 (98) 67 (100) 147 (99)
VR came out since last visit
Never 75 (88) 65 (94) 140 (91) 79 (93) 65 (93) 144 (93) 75 (91) 67 (100) 142 (95)
1 time 10 (12) 4 (6) 14 (9) 5 (6) 5 (7) 10 (6) 6 (7) – 6 (4)
2 times – – – 1 (1) – 1 (1) 1 (1) – 1 (1)
Duration of ring removal(s)
Less than 1 day 80 (95) 69 (100) 149 (97) 80 (95) 69 (99) 149 (97) 77 (94) 67 (100) 144 (97)
1 day or more 4 (5) – 4 (3) 4 (5) 1 (1) 5 (3) 5 (6) – 5 (3)
VR came out on its ownc
6 (43) 7 (64) 3 (38)
During defecation – 1 (14) –
During urination – 1 (14) 1 (33)
During sex 2 (40) – –
After sex – – –
During/after physical exertion – – –
Menses-related 1 (20) 4 (57) 2 (67)
Other 2 (40) 1 (14)
Participant removalc
8 (57) 4 (36) 5 (63)
During defecation – 1 (14) –
During urination – 1 (14) 1 (33)
During sex 2 (40) – –
After sex – – –
During/after physical exertion – – –
Menses-related 1 (20) 4 (57) 2 (67)
Other 2 (40) 1 (14)
Reason for removalc
Causing discomfort 1 (13) – –
Felt it was not in place – – –
Didn’t want partner to know about it – – –
Partner told me to remove it 2 (25) – –
Menses-related 2 (25) 1 (25) 1 (20)
Other 3 (38) 3 (75) 4 (80)
Action taken after VR outc
Washed, rinsed, reinserted 9 (82) 7 (64) 5 (71)
Reinserted without washing or rinsing 1(9) – –
Left it out and reinserted before next appt – – –
Contacted clinic – 2 (18) 1 (14)
Waited for next appt 1 (9) 2 (18) 1 (14)
VR vaginal ring, FU follow-up
a
Weeks and visit refer to period of time on VR; therefore, Week 4 FU for Groups A and B are visits 3 and 7, respectively; Week 8 FU is visits 4
and 8 (A and B), and Week 12 FU is visits 5 and 9
b
Only includes participants who responded to FAQ #6 at all three FU visits
c
Only includes women reporting a ring removal
1792 AIDS Behav (2012) 16:1787–1798
123

8. Women reported that the VR was generally unnoticeable
and easy to use; therefore, they had few problems being
adherent.
Most of the men said their partners did not take the VR
out during the study period. Many women who did not
remove the VR said they were told not to do so as part of
the study protocol. One woman from the Durban site said
that she refused to take the VR out upon her partner’s
request. She told him:
…no you cannot see it because the doctor inserts me
so I mustn’t take it out.
Some of the men said that their partners told them they
must not take it out until the end of the study, whereas
other men said they did not know if their female partners
took out the VR, as they did not discuss this issue. A
woman at the Johannesburg site described her intention to
retain the VR, even if it negatively influenced sex with her
partner:
I asked him: ‘‘What will happen if the ring affects our
sex life?’’ Then he said when it happens like that, I
will (have to) take the ring out, the ring will never
spoil something that he likes. Then I said ‘‘m’kay
fine’’. I told him that if it spoils our sex life he will
wait until I finish three months.
Vaginal Ring Removals and Expulsions
At each follow-up visit, the majority of participants (range
88–100 %) reported no VR removals or expulsions since
their last visit, and the number of women reporting at least
one removal or expulsion at each visit decreased over time:
14, 10, and 6 women at Weeks 4, 8, and 12, respectively
(Table 2). Four women reported multiple removals or
expulsions, and three women reported these at more than
one visit. Thus, across all visits, there were 34 total VR
removals or expulsions among 28 individuals. The 33 of 34
events (97 %) for which data were available were evenly
attributed to voluntary (VR removal) and involuntary (VR
expulsion) circumstances (48 vs. 52 %, Table 2).
In the quantitative data, menses-related reasons were the
most commonly reported circumstances surrounding
expulsions (involuntary removals), while those occurring
because of defecation or urination, or during sex were
described less frequently (Table 2). Similarly, menses was
also the most frequent reason reported for women who
removed the VR voluntarily. Open-ended questionnaire
responses classified as ‘‘menses-related’’ included reasons
for removal due to: heavy bleeding during menses; a desire
to clean the ring during or after menses; and participant
misperception that the ring should be removed during
menses. The topic of VR use and menses was not included
in the qualitative interview guides, and thus not systemat-
ically explored, however one woman described taking the
VR out during menses to clean it and then reinsert it.
Additionally, in the questionnaires, ten women provided
reasons for VR removal that did not clearly correspond
with the answer choices provided (Table 2). These were
cleaning VR (which may or may not have been menses-
related, 2 women), showing VR to partner (1 woman), fear
of VR causing damage (1 woman), investigating discharge
or smell (2 women), having an infection (2 women), and
simply checking if the VR was there (2 women). Most
women (72 %) washed, rinsed, and reinserted the VR after
it was out of the vagina. Between one and three participants
at each visit reported that they waited until their next
appointment before reinserting the VR.
In the qualitative data the most common description of the
circumstances surrounding ring removals were related to
disclosure of ring use to male partners, and consequent
reactions. This theme arose in all FGDs, and approximately
half of the men reported in IDIs that they were shown their
partner’s VR. For example, women and men described sit-
uations where the men asked their female partners to remove
the VR so they could see it. One man said that he did not
believe his partner had a VR, because he could not feel it
during sex, and asked her to show it to him. Another woman
described that her partner insisted she stop wearing the VR.
Corroborating the above report that men cannot feel the VR,
she told him that she had removed it when in actuality she
kept the VR in her vagina the entire study period. Several
men said that their partners removed the VR only towards the
end of the study, and reinserted it immediately having no
difficulty doing so. One of the men at the Moshi site said:
…what happen is that she informed and showed me the
ring on the last day before returning it to the clinic.
At least one woman in each FGD expressed concerns
that the VR might be spontaneously expelled from their
vagina during sex or when they urinated or defecated. That
said, only one woman in the focus groups (from Johan-
nesburg), discussed her actual experience with a sponta-
neous expulsion:
That morning when I went to the toilet it was too
much [(menstrual) blood that came out and I was
scared…Then I went to the clinic to tell them the ring
might have come out because I didn’t feel it anymore.
…when they checked me they found that the ring is
out, then inserted another ring.
Predictors of Adherence
In the bivariate analyses, several variables were signifi-
cantly associated with being ‘‘perfectly adherent’’ at the
AIDS Behav (2012) 16:1787–1798 1793
123

9. p 0.05 level, including study group, having no concerns
about the VR coming out, never experiencing emotional
problems with the VR, and ever having unprotected sex
during the study (Table 3). Seven additional variables were
associated with adherence at the p 0.20 level, and these
were retained for consideration (aside from two variables
which had zero count cells). In the final multivariate model,
three predictors were significantly associated with the
outcome of ‘‘perfect adherence’’ at the p 0.05 level:
women in study group A were significantly less likely to
report being perfectly adherent (AOR 0.21, 95 % CI
0.07–0.64, p 0.01), as were those who reported baseline
use of vaginal products for menstrual control (AOR 0.22,
95 % CI 0.05–0.89, p = 0.03). Compared with the partic-
ipants at the Cape Town site, participants at the Johan-
nesburg and Moshi sites were more likely to report perfect
adherence.
Discussion
Microbicides formulated as VRs are being investigated as
potentially effective HIV prevention technologies. Because
the VR is worn continuously for up to a month without
removal, one important advantage is that, hypothetically, it
could enable women to be more adherent to prophylactic
treatment. This study of placebo VR use for 12 weeks
would appear to corroborate that assumption: the majority
(82 %) of women reported that they never took the VR out,
and [95 % of participants across visits and across groups
reportedly wore it every day they were meant to for at least
12 h. These results are concordant with reports from other
female-initiated HIV prevention method research, such as
the vaginal diaphragm and the DuetÒ cervical barrier,
where reported uptake and correct and consistent use was
high among African women, despite the novelty of the
products [25, 26]. That said, self-reported adherence to the
diaphragm and DuetÒ—even when the latter was used
continuously—was lower than reported here. The first
microbicide study to demonstrate proof of concept,
CAPRISA 004, reported a higher level of product effec-
tiveness (54 vs. 39 % overall) among participants catego-
rized as ‘‘high adherers’’([80 %), highlighting the critical
importance of identifying products and strategies to enable
high adherence to product [5].
Twenty-eight (16 %) of the women in this study self-
reported at least one VR removal or expulsion during the
course of participation. However, most VR removals that
did occur were for 12 h or less, which is a period of time
that might not negatively impact drug delivery in future
studies with active agents, depending on the product.
Many of the reported VR expulsions and removals were
related to menses; for example, heavy blood flow or
menstrual control products causing the VR to come out, or
concern about the VR becoming dirty or retaining odor,
leading to removal. In this study women were instructed
not to remove the ring, and instructions or culturally-sen-
sitive counseling for how to balance this instruction with
menses were not explicitly provided. While the majority of
VR removals—whether menses-related or otherwise—
were for short periods of time, these data underscore the
importance of developing clearer counseling messages in
future studies around VR removal or expulsions, including
hygiene practices and allowable amount of time for
removal and reinsertion.
In a qualitative exploratory study among female sex
workers and male clients in Kenya, similar concerns about
VR use during menses were reported when attitudes about
potential future use of VRs for HIV prevention were dis-
cussed, although most participants felt that VR use during
menses would not be a problem [27]. In that study, other
potential hygiene considerations warranting VR removals
were described, such as washing the VR between partners.
This concern was not raised by male or female participants
in the current study, but warrants evaluation in future
research with sex workers or women having multiple
concurrent partners.
FGD and IDI respondents frequently spoke of removing
the VR to show it to their male partner. Only one woman
reported this in the quantitative data, perhaps because
women underreported VR removals, or because this was
not a predesignated response category. Alternatively, in the
FGD, this may have been a more socially acceptable way
to explain removals than other reasons. Most studies
examining the acceptability and context of female-initiated
HIV prevention method use have emphasized the impor-
tance of disclosing use to a male partner [28], including
data from the exploratory VR study in Kenya described
above [27] and acceptability results from this study [19],
which underscore the importance of involving male part-
ners in women’s HIV prevention methods in this cultural
setting.
The qualitative data highlight ways in which the study
context could have a positive impact on adherence to
product. For example, refusing to remove the VR because
the ‘‘doctor’’ inserted it seems to reflect a high level of trust
between the study’s medical staff and the study partici-
pants. In addition, women showed a commitment to study
participation and the study protocol when they reported
defying their partner’s requests to remove the VR.
In multivariate analysis, women who reported previous
use of vaginal products for menstrual control at baseline
were significantly less likely to be perfectly adherent. One
hypothesis is that women who have experienced inserting
vaginal products would be more willing or successful VR
users. Indeed, the association between tampon use and
1794 AIDS Behav (2012) 16:1787–1798
123

10. Table 3 Unadjusted and adjusted factors associated with ‘‘perfect adherence’’ to vaginal ring use (n = 147)
Perfectly
adherent
(n = 120)
Not
perfectly
adherent
(n = 27)
UOR AORa
n % n % est 95 % CI p value est 95 % CI p value
Demographic and sexual behavior characteristic (baseline)
Ageb
NA NA NA NA NA NA 0.90
Race
Black 116 96.7 25 92.6 2.32 0.40–13.37 0.30
Indian/cape colored 4 3.3 2 7.4
Marital status
Married vs. not married 39 32.5 5 18.5 2.12 0.75–6.01 0.17 0.69 0.18–2.60 0.58
Has main sex partner
Yes vs. No 118 98.3 26 96.3 2.27 0.20–25.98 0.46
Number of sex partners in past 3 months
1 vs. 2? 32 26.9 9 33.3 0.74 0.30–1.80 0.49
Perceived risk of HIV compared to others
High vs. same or lower than others 17 14.4 1 3.7 4.38 0.56–34.42 0.20 5.22 0.53–51.55 0.16
Ever used male condom
Yes vs. No 96 80.0 25 92.6 0.32 0.07–1.45 0.17 1.06 0.14–7.87 0.95
Condom use in past 7 days with main partner
Every time had sex 58 48.3 18 66.7 2.36 0.81–6.89 0.22
Not every time had sex 38 31.7 5 18.5 Ref Ref
No sex 24 20.0 4 14.8 1.86 0.57–6.08
Previously participated in microbicide study
Yes vs. No 52 43.3 14 51.9 0.71 0.31–1.64 0.52
Use of vaginal products
For cleaning 19 15.8 2 7.4 2.35 0.51–10.77 0.37
For menstruation 12 10.0 6 22.2 0.39 0.13–1.15 0.10 0.22 0.05–0.89 0.03
For sex: to make vagina dryer, wetter, tighter, nicer
smelling, or to lubricate condom
6 5.0 2 7.4 0.66 0.13–3.45 0.64
For healing or treating 12 10.0 2 7.4 1.39 0.29–6.60 1.00
For pregnancy prevention 3 2.5 1 3.7 0.67 0.07–6.67 0.56
For any of the above purposes 36 30.0 10 37.0 0.73 0.30–1.74 0.50
Site
Moshi 45 37.5 3 11.1 7.50 1.53–36.67 0.01 8.59 1.00–73.38 0.05
Johannesburg 36 30.0 9 33.3 2.00 0.55–7.33 0.83 6.23 1.21–32.17 0.03
Durban 29 24.2 10 37.0 1.45 0.39–5.28 0.26 2.42 0.47–12.46 0.29
Cape Town 10 8.3 5 18.5 Ref Ref Ref Ref Ref
Study group
A (VR ? no VR) vs. B (no VR ? VR) 60 50.0 20 74.1 0.35 0.14–0.89 0.03 0.21 0.07–0.64 0.01
Sexual behavior, product attitudes and use (at exit)
Sex protected by male condoms
Always protected or never had sex vs. not always
protected
64 54.7 21 77.8 0.35 0.13–0.92 0.03 0.46 0.11–1.82 0.27
Likes having VR in place every day
Yes/Sometimes vs. No 116 96.7 24 92.3 2.42 0.42–13.95 0.29
Ever had concerns about VR coming out
Yes/sometimes vs. No 23 19.2 11 40.7 0.34 0.14–0.84 0.02 0.77 0.23–2.61 0.68
Ever had concerns about losing VR inside body
AIDS Behav (2012) 16:1787–1798 1795
123

11. preference for use of the contraceptive NuvaRingÒ was
cross-sectionally reported in one US study; [29] however,
previous tampon use was not associated with VR satis-
faction among women in a small randomized trial
(n = 201) in New York City [30]. Alternatively women
previously experienced with tampons are comfortable with
vaginal insertions and removals, and/or may not want to
discontinue this menstrual control practice, which could
explain our finding.
Combined with other data from this study, our results
suggest the need for enhanced counseling and instruction
about management of menses and VR use in future studies.
Counselors could also build on the premise that women
who are accustomed to inserting tampons or other absor-
bent products vaginally might be more likely to remove the
VR to continue this practice—even if a protocol contrain-
dicates this practice. This finding signals the need for
future research about concomitant use of microbicidal VRs
and tampons to investigate if VR efficacy is compromised
by intravaginal product use [31].
The multivariate results in this study offer an additional
interesting insight into study design. In this crossover study,
women in Group A received the VR first, whereas women in
Group B had an initial 12 weeks of nonuse. During the first
12 weeks, 11 women in Group B were discontinued for pro-
tocol noncompliance or other issues prior to initiating VR use.
Consequently, thesubsetofwomenenrolledintoGroupB was
selectively more (protocol) adherent prior to initiation of their
VR use, and they were found to be significantly more product
adherent. This suggests that adherence in future studies may
benefit from ‘‘run-in’’ periods that eliminate participants who
demonstrate noncompliance to either a secondary product or
to the protocol. On the other hand, it should be cautioned that
exclusion of noncompliant study participants is likely to
introduce a selection bias towards higher estimates of adher-
ence. While this may be necessary to establish ‘‘proof-of-
concept’’ for efficacy, the effectiveness of an active VR will
need to evaluate use under more ‘‘real-world’’ conditions
where women may be unable to regularly attend clinic visits.
This study has several limitations. First and foremost,
because this study was designed as a preliminary safety and
acceptability study to inform future research, the VR did
not contain an active agent. Removals associated with
actual or perceived side effects of an antiretroviral drug or
with perceived efficacy of an investigational product, may
change this behavior in either direction. Thus, it is
unknown how adherence to product may have been biased
in either direction because of this. Similarly, because ring
use in this study was limited to 12 weeks, it is also
unknown how ring use may change in either direction with
longer duration of use, and this will be an important
measurement in upcoming clinical trials. Several
Table 3 continued
Perfectly
adherent
(n = 120)
Not
perfectly
adherent
(n = 27)
UOR AORa
n % n % est 95 % CI p value est 95 % CI p value
Yes vs. No 34 28.3 13 48.2 0.43 0.18–1.00 0.07 0.35 0.10–1.21 0.10
Ever experienced physical problems with VR
Yes vs. No 4 3.3 3 11.1 0.28 0.06–1.31 0.12 0.42 0.06–3.09 0.40
Ever experienced any problems with study
Yes vs. No 0 0 1 3.7 0 0.18c
Ever experienced emotional problems with VR
Yes vs. No 0 0 2 7.4 0 0.03c
Partner knew about study
Prior to start of VR use vs. After VR use initiated or
never
95 79.2 18 66.7 1.9 0.76–4.74 0.21 1.26 0.39–4.08 0.70
Ever used any intravaginal products during study
Yes vs. No 6 5.0 1 3.7 1.37 0.16–11.86 1.00
VR vaginal ring, UOR unadjusted odds ratio, AOR adjusted odds ratio
‘‘Perfect adherence’’ is defined as participants who had the VR inserted at the start of the 12-week regimen and removed at the end, with no
interim removals
Only includes participants who have data from all three follow-up visits during VR regimen
a
Includes variables significant in unadjusted analyses at the p 0.20 level, except variables with zero cells
b
Age was treated as a continuous variable; therefore n, %, and odds ratios were not computed. P-value for the difference between groups was
computed using the Wilcoxon test
1796 AIDS Behav (2012) 16:1787–1798
123

12. contraceptive ring studies have reported discontinuation
rates of 17–32 % over the course of a year [32]. Second,
although directly observed assessment of VR presence or
removal was done at each clinic visit, interim removals and
consistent use could not be physically verified. Therefore,
adherence measures relied on self-report of VR use in
adherence questionnaires, and these data may be subject to
recall and social desirability bias. Third, although the
qualitative data corroborate much of the quantitative find-
ings, there were some clear differences, and this may
reflect limitations of each of the methodologies. For
example, menses-related removals were the most fre-
quently cited reasons in the quantitative data for removal or
expulsion. However, women in the FGDs were not sys-
tematically asked about VR removal during menses,
because the study team did not recognize, a priori, that
menses would be an important reason for ring removals.
Consequently, exploration of this topic was not included in
the qualitative interview guides and only one woman each
described expulsion or removal during menses. Finally, as
with most studies of this nature, the women who enrolled,
the women who agreed to additionally participate in FGD
and have their partners be contacted, as well as the men
who agreed to IDI, may be different in important ways than
the general population.
In summary, African women in this study reported high
levels of VR use: 82 % never removed the VR for the
entire 12-week period of use, and overall[95 % of women
wore the VR every day for at least 12 h. VR removals and/
or expulsions were reported by approximately one-fifth of
the participants, and these were most commonly associated
with menstrual flow management or menses-related
hygiene concerns. At the research sites in the present study,
most participants were sexually active during their VR
regimen. Consequently, in the context of high HIV risk
exposure, these data suggest that a prevention method that
is simple to use, requires minimal action for adherence, and
can comfortably be worn during normal daily activities and
during sex, should enable high adherence (and conse-
quently more accurate assessment of safety and efficacy) in
clinical trials, as well as wider public health impact if
proven effective or partially effective.
Acknowledgments The authors would like to acknowledge the IPM
011 study participants and research staff at all participating
organizations.
References
1. UNAIDS. UNAIDS Reports on the Global AIDS Epidemic 2010.
Available from http://www.unaids.org/globalreport/default.htm.
Accessed 19 Dec 2011.
2. Malcolm RK, Edwards KL, Kiser P, Romano J, Smith TJ.
Advances in microbicide vaginal rings. Antiviral Res. 2010;88
(Suppl 1):S30–9.
3. Nel A, Smythe S, Young K, Malcolm K, McCoy C, Rosenberg Z,
et al. Safety and pharmacokinetics of dapivirine delivery from
matrix and reservoir intravaginal rings to HIV-negative women.
J Acquir Immune Defic Syndr. 2009;51:416–23.
4. Romano J, Variano B, Coplan P, Van Roey J, Douville K,
Rosenberg Z, et al. Safety and availability of dapivirine
(TMC120) delivered from an intravaginal ring. AIDS Res Hum
Retroviruses. 2009;25(5):483–8.
5. Karim QA, Karim SA, Frohlich J, Grobler A, Baxter C, Mansoor
L, et al. Effectiveness and safety of tenofovir gel, an antiretroviral
microbicide, for the prevention of HIV infection in women.
Science. 2010;329(5996):1168–74.
6. Grant R, Lama J, Anderson P, McMahan V, Liu A, Vargas L,
et al. Preexposure chemoprophylaxis for HIV prevention in men
who have sex with men. New Engl J Med. 2010. doi:10.1056/
NEJMoa1011205.
7. Weiss RA. HIV receptors and the pathogenesis of AIDS. Science.
1996;272(5270):1885–6.
8. Institute of Medicine. Methodological challenges in biomedical
HIV prevention trials. Institute of Medicine. 2008. Available
from: http://www.iom.edu/Reports/2008/Methodological-Chall-
enges-in-Biomedical-HIV-Prevention-Trials.aspx. Accessed 19
Dec 2011.
9. Microbicide trials network statement on decision to discontinue
use of oral Tenofovir tablets in VOICE, a major HIV prevention
study in women. Microbicide Trials Network. 2011.
10. Microbicide trials network statement on decision to discontinue
use of Tenofovir gel in VOICE, a major HIV prevention study in
women. 2011.
11. FHI statement on the FEM-PrEP HIV prevention study: FHI to
initiate orderly closure of FEM-PrEP. FHI 2011.
12. van der Straten A, Van Damme L, Haberer JE, Bangsberg DR.
How well does PREP work? Unraveling the divergent results of
PrEP trials for HIV prevention. AIDS 2012;26(7):F13–F9.
13. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J,
Kapiga S, et al., editors. The FEM-PrEP trial of emtricitabine/
tenofovir disoproxil fumarate (Truvada) among African Women.
The 19th Conference on Retrovirus and Opportunistic Infections.
Seattle; 5–8 March 2012.
14. Hardy E, Hebling EM, Sousa MH, Almeida AF, Amaral E.
Delivery of microbicides to the vagina: difficulties reported with
the use of three devices, adherence to use and preferences.
Contraception. 2007;76(2):126–31.
15. de la Nova´k A, Loge C, Abetz L, van der Meulen EA. The
combined contraceptive vaginal ring, NuvaRing: an interna-
tional study of user acceptability. Contraception. 2003;67(3):
187–94.
16. Dieben T, Roumen F, Apter D. Efficacy, cycle control, and user
acceptability of a novel combined contraceptive vaginal ring.
Obstet Gynecol. 2002;100(3):585–93.
17. Gilliam ML, Neustadt A, Kozloski M, Mistretta S, Tilmon S,
Godfrey E. Adherence and acceptability of the contraceptive ring
compared with the pill among students: a randomized controlled
trial. Obstet Gynecol. 2010;115(3):503–10.
18. Nel A, Young K, Romano J, Woodsong C, Montgomery E,
Masenga G, et al. Safety and acceptability of silicone elastomer
vaginal rings as potential microbicide delivery method in African
Women. 18th Conference on Retroviruses and Opportunistic
Infections. 2011(Paper #1004).
19. van der Straten A, Montgomery E, Cheng H, Wegner L, Masenga
G, von Mollendorf C, et al. High acceptability of a vaginal ring
intended as a microbicide delivery method for HIV prevention in
African Women. AIDS Behav. 2012.
AIDS Behav (2012) 16:1787–1798 1797
123

13. 20. Nel A, Young K, Romano J, Woodsong C, van der Straten A,
Masenga G, et al. Safety and acceptability of silicone elastomer
vaginal rings as potential microbicide delivery method in African
women. International partnership for microbicides; Silver Spring,
MD, 2011.
21. Simons-Rudolph A, Woodsong C, Koo H. Modeling the social
context of microbicide use. Microbicide Q. 2008;6(4):1–11.
22. Woodsong C, Alleman P. Sexual pleasure, gender power and
microbicide acceptability in Zimbabwe and Malawi. AIDS Educ
Prev. 2008;20(2):171–87.
23. Sahin-Hodoglugil N, Montgomery E, Kacanek D, Morar N,
Mtetwa S, Nkala B, et al. User experiences and acceptability
attributes of the diaphragm and lubricant gel in an HIV preven-
tion trial in Southern Africa: a theory based qualitative analysis
(under review). 2010.
24. Woodsong C, Simons-Rudolph A, Alleman P. A comprehensive
and flexible conceptual framework for investigating acceptability
in microbicide clinical trials (Poster Presentation). Microbicides.
Delhi 2008.
25. Montgomery ET, Blanchard K, Cheng H, Chipato T, de Bruyn G,
Ramjee G, et al. Diaphragm and lubricant gel acceptance, skills
and patterns of use among women in an effectiveness trial in
Southern Africa. Eur J Contracept Reprod Health Care. 2009;
14(6):410–9.
26. Montgomery ET, Woodsong C, Musara P, Cheng H, Chipato T,
Moench TR, et al. An acceptability and safety study of the DuetÒ
cervical barrier and gel delivery system in Zimbabwe. J Int AIDS
Soc. 2010;13:30.
27. Smith DJ, Wakasiaka S, Hoang TD, Bwayo JJ, Del Rio C, Priddy
FH. An evaluation of intravaginal rings as a potential HIV pre-
vention device in urban Kenya: behaviors and attitudes that might
influence uptake within a high-risk population. J Womens Health
(Larchmt). 2008;17(6):1025–34.
28. Montgomery E, van der Straten A, Chidanyika A, Chipato T,
Jaffar S, Padian N. The importance of male partner involvement
for women’s acceptability and adherence to female-initiated HIV
prevention methods in Zimbabwe. AIDS Behav. 2010;epub ahead
of print. doi:10.1007/s10461-010-9806-9.
29. Tepe M, Mestad R, Secura G, Allsworth JE, Madden T, Peipert
JF. Association between tampon use and choosing the contra-
ceptive vaginal ring. Obstet Gynecol. 2010;115(4):735–9.
30. Schafer J, Osborne L, Davis A, Westhoff C. Acceptability and
satisfaction using Quick Start with the contraceptive vaginal ring
versus an oral contraceptive. Contraception. 2006;73:488–92.
31. Verhoeven CH, Dieben TO. The combined contraceptive vaginal
ring, NuvaRing, and tampon co-usage. Contraception. 2004;69(3):
197–9.
32. Madden T, Blumenthal P. Contraceptive vaginal ring. Clin Obstet
Gynecol. 2007;50(4):878–85.
1798 AIDS Behav (2012) 16:1787–1798
123
View publication statsView publication stats