Safety and Adherence to Intermittent Pre-Exposure
Prophylaxis (PrEP) for HIV-1 in African Men Who Have
Sex with Men and Female Sex Workers
Gaudensia Mutua1., Eduard Sanders2,3., Peter Mugo2, Omu Anzala1, Jessica E. Haberer4,
David Bangsberg4, Burc Barin5, James F. Rooney6, David Mark7, Paramesh Chetty8, Patricia Fast7,
Frances H. Priddy7*
1Kenya AIDS Vaccine Initiative, University of Nairobi, Nairobi, Kenya, 2Kenya Medical Research Institute, Kilifi, Kenya, 3Nuffield Department of Medicine, University of
Oxford, Headington, United Kingdom, 4Massachusetts General Hospital Center for Global Health, Boston, Massachusetts, United States of America, 5The EMMES
Corporation, Rockville, Maryland, United States of America, 6Gilead, Foster City, California, United States of America, 7International AIDS Vaccine Initiative, New York,
New York, United States of America, 8International AIDS Vaccine Initiative, Johannesburg, South Africa
Background: Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible
than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen
among Kenyan men who have sex with men (MSM) and female sex workers (FSW).
Methods/Principal Findings: MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday,
Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers
were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS).
Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-
month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups.
Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing
(p=0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have
impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen.
Conclusions/Significance: Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent
doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP
if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing
and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better
methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable
to more standard regimens.
Trial Registration: ClinicalTrials.gov NCT00971230
Citation: Mutua G, Sanders E, Mugo P, Anzala O, Haberer JE, et al. (2012) Safety and Adherence to Intermittent Pre-Exposure Prophylaxis (PrEP) for HIV-1 in
African Men Who Have Sex with Men and Female Sex Workers. PLoS ONE 7(4): e33103. doi:10.1371/journal.pone.0033103
Editor: Gary Maartens, University of Cape Town, South Africa
Received August 25, 2011; Accepted February 3, 2012; Published April 12, 2012
Copyright: ? 2012 Mutua et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded and sponsored by the International AIDS Vaccine Initiative (IAVI). Support in the form of study medication was provided by
Gilead Sciences. As the sponsor, IAVI reviewed and approved the study design, data collection and analysis, decision to publish and the manuscript. As Gilead
Sciences employ James F. Rooney, they have participated in study design and preparation of the manuscript but played no role in data collection and analysis or
decision to publish.
Competing Interests: Burc Barin is employed by a commercial statistical group, The EMMES Corporation. James F. Rooney is employed by a commercial funder
of this study, Gilead Sciences, which supplied the active drug and placebo tablets used in this study. Gilead Sciences developed and markets the drug, Truvada,
used in this trial for HIV treatment. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
. These authors contributed equally to this work.
Recent studies indicate the widespread presence of MSM
groups in Africa with high rates of HIV infection, HIV risk
behavior and linkages to heterosexual networks . Heterosexual
transmission of HIV remains the predominant mode of transmis-
sion in Kenya, however up to 15% of all new infections are
estimated to be directly attributable to men who have sex with
men (MSM) . Recently, the use of oral antiretroviral pre-
exposure prophylaxis (PrEP) was shown to be effective in
preventing HIV in MSM: the iPrEX study of approximately
2500 MSM and transgender women demonstrated a 44%
reduction in the incidence of HIV following daily use of the fixed
dose combination pill, Truvada, containing emtricitabine and
PLoS ONE | www.plosone.org1 April 2012 | Volume 7 | Issue 4 | e33103
tenofovir disoproxil fumarate (FTC/TDF) . Efficacy correlated
closely with drug adherence and drug levels. Pill use on 90% or
more of days was associated with 73% efficacy, while detectable
drug levels were associated with 92% efficacy. Early in 2011, the
US Centers for Disease Control published interim guidance for the
use of PrEP in MSM . PrEP was also shown to be effective in
other at-risk populations. Two studies of daily PrEP with either
FTC/TDF or TDF alone in HIV serodiscordant couples and in
young men and women in sub-Saharan Africa found that daily
FTC/TDF or TDF alone reduced HIV incidence by 62–73%
(Baeten J, Celum C. (2011) Antiretroviral Pre-Exposure Prophy-
laxis for HIV-1 prevention among heterosexual African men and
women: the Partners PrEP Study [Abstract MOAX0106]. 6th IAS
Conference on HIV Pathogenesis, Treatment and Prevention; 17–
20 July 2011; Rome, Italy. Available: http://pag.ias2011.org/
flash.aspx?pid=886. Accessed 14 March 2012. Thigpen MC,
Kebaabetswe PM, Smith DK, Segolodi TM, Soud FA, et al. Daily
oral antiretroviral use for the prevention of HIV infection in
heterosexually active young adults in Botswana: results from the
TDF2 study. [Abstract WELBC01]. 6th IAS Conference on HIV
Pathogenesis, Treatment and Prevention; 17–20 July 2011; Rome,
Italy. Available: http://pag.ias2011.org/abstracts.aspx?aid=4631.
Accessed 14 March 2012.)
In contrast, a study of daily PrEP using FTC/TDF in at-risk
women failed to find a reduced risk of HIV infection in the
treatment group . The possible biologic and behavioral reasons
for lack of efficacy among women in this trial are under
investigation. However, the prospect of keeping healthy individ-
uals on lifelong chemoprophylaxis presents unique challenges in
drug adherence and the potential for drug toxicity . Critics of
PrEP have also expressed concern about the cost of keeping a large
population of HIV-uninfected people on chronic treatment, as
well as the potential for HIV risk behavior compensation . Both
FTC and TDF are licensed for use by HIV-infected patients and
have favorable safety profiles .
Reducing the frequency of administration by intermittent rather
than daily use could mitigate concerns about toxicity and cost. The
long intracellular half-lives of TDF and FTC, 40–60 hours,
present this theoretical possibility [9,10]. A macaque challenge
study demonstrated that intermittent TDF/FTC PrEP offered
comparable protection to daily PrEP against rectal transmission of
SHIV . However little is known about adherence to and
acceptability of intermittent PrEP regimens in HIV at-risk groups.
In particular, preference for and adherence to fixed doses (i.e. once
weekly or twice weekly) versus post-coital dosing is unknown. Of
interest for HIV vaccine development, PrEP may also have the
potential to allow development of effective HIV-specific immune
responses in people with repeated mucosal exposures who do not
become infected. Several animal studies have shown higher rates
of SIV-specific immune responses in PrEP treated animals that
were protected from SIV infection or that controlled infection
In this study, which was initiated and completed prior to the
release of any PrEP efficacy results from studies cited above, we
compared safety and drug adherence between daily and
intermittent PrEP regimens of FTC/TDF. The intermittent PrEP
regimen was defined as a twice-weekly dosing plus a coitally-
dependent dose. We focused on MSM due to the high and
ongoing burden of new HIV infections in this population, but
included a limited number of FSW to help avoid community
identification of the study as MSM-exclusive. In addition, we
investigated the concept that suppression of viral replication by
PrEP during repeated mucosal exposures may allow the
development of effective anti-HIV immune responses.
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Two centers in Kenya (Kenya AIDS Vaccine Initiative [KAVI]-
Kangemi in Nairobi, and Center for Geographic Medicine
Research – Coast [GMRC]-KEMRI in Kilifi) were among the
first in Africa to develop MSM cohort studies with very high HIV-
1 incidence (,9% per 100 person years observation), largely
determined by unprotected receptive anal intercourse . Kenya
has now made interventions for MSM a key priority in their
national HIV strategic plan  and centers in Nairobi and Kilifi
are providing a comprehensive HIV prevention package to at-risk
research volunteers, including regular HIV testing and risk
reduction counseling, provision of male condoms and water-based
lubricants, screening and treatment of sexually transmitted
infections and referral for adult male circumcision for men
practicing heterosexual sex. FSW are also followed at the centers.
Volunteers were recruited from ongoing HIV prevention cohorts
at the two centers. HIV-uninfected MSM and FSW aged 18–49
years who reported at least one of the following risk criteria in the
past 3 months were enrolled in the study: current or previous STI,
multiple episodes of unprotected vaginal or anal sex, or engaging
in transactional sex. Volunteers with chronic hepatitis B infection
(HBsAg-positive) or with creatinine clearance ,80 mL/min and
pregnant or lactating mothers were excluded due to study drug
toxicity concerns. Women of childbearing potential were required
to use a non-barrier form of contraception (hormonal contracep-
tion or intrauterine device) during study participation.
Community stakeholder consultations
Both centers conduct regular community stakeholder consulta-
tions on new and ongoing research and have active community
advisory boards. Study participation was discussed in small groups
of 6–8 cohort volunteers at both centers. Community advisory
boards at both centers reviewed study aims of the protocol and
provided feedback on potential community concerns.
All volunteers gave written informed consent to participate in
the study. The study was approved by the Kenyatta National
Hospital Ethics Review Committee and the Kenya Medical
Research Institute Ethics Review Committee.
Volunteers were randomized to daily FTC/TDF or placebo, or
intermittent (fixed dose on Mondays, Fridays and post-coital dose
within 2 hours after sex, not to exceed 1 dose per day) FTC/TDF
or placebo in a 2:1:2:1 ratio, and followed monthly with
standardized adherence and risk reduction counseling, HIV
testing, and safety evaluation for 4 months. Adherence rate was
assessed by the medication event monitoring system (MEMS), in
which each opening of the pill bottle is recorded electronically, and
by monthly self-report using a timeline followback interview
calendar [22–24]. Briefly, the calendar is used to prompt recall of
recent behavior and has been used successfully in other behavioral
studies. Volunteers were given a key chain pill holder for portable
dosing and were instructed to load the holder with a couple of pills
if they felt that they could not carry the pill bottle with MEMS cap.
Sexual activity data were collected via daily short message service
(SMS) text message queries, as well as through the timeline
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followback face-to-face risk assessment with a monthly recall
period. Volunteers were provided with free mobile phones, SIM
cards and airtime credits, as well as condoms and water-based
The objectives of the study were (1) to evaluate the safety of
daily and intermittent dosing of FTC/TDF; (2) to compare the
acceptability of and adherence to daily and intermittent PrEP
regimens; (3) to evaluate changes in HIV-associated risk behavior;
and (4) to evaluate HIV-specific immune responses in volunteers
randomized to FTC/TDF and placebo.
The main outcome measures were (1) clinical adverse events
including mild, moderate and greater severity renal toxicities and
serious adverse events, (2) willingness to use the study regimen, if
shown to be effective, (3) adherence rates for daily and intermittent
dosing, (4) change in HIV-associated risk behavior during trial
participation, (5) the proportion of volunteers with HIV-specific
immune responses as measured by Interferon-c ELISpot.
Seventy-two volunteers were randomized to daily and intermit-
tent FTC/TDF regimens (24 active and 12 placebo recipients per
group). Because this was an exploratory study to evaluate safety,
adherence and acceptability of intermittent PrEP, it was
understood at the outset that this study had limited power to
rule-out smaller differences in safety and adherence. For example,
with 24 volunteers assigned to either daily or intermittent FTC/
TDF, if no drug-related serious toxicities were observed, the upper
limit of the two-sided exact 95% confidence interval for the
corresponding true incidence was 14.3%. Therefore, observing no
drug-related severe toxicities provided 97.5% confidence that the
true incidence was no more than 14.3%. With 36 volunteers
assigned to active and placebo for each regimen, the study had
51% power to detect an adherence rate of 90% for each regimen.
Assuming condoms are used always or frequently (more than half
the time) by 60% of volunteers at baseline, the study had .80%
power to detect a 50% decrease in condom usage by treatment
A random allocation sequence was generated by an external
data coordinating center. Study product was randomly assigned in
mixed blocks of 3 and 6, and the dosing schedule randomly
assigned within study product using a block size of 2, stratified
according to site. Investigators at the study sites enrolled
volunteers via an electronic enrollment system (administered by
the data coordinating center), where allocation codes were
assigned consecutively to eligible volunteers at the time of first
dispensation of study drug.
Allocation to FTC/TDF or identical placebo pill was blinded to
study volunteers, all research staff and the study sponsor.
Allocation to daily or intermittent dosing was not blinded.
The unadjusted monthly MEMS adherence for the daily group
was calculated as the number of MEMS events in 28 days divided
by 28 days. Both the monthly self-report of curiosity openings
(openings without removing pills) and monthly self-report of
pocket doses (removal of multiple pills at one opening) were used
to estimate adjusted MEMS adherence. The number of curiosity
openings was subtracted from the number of MEMS openings,
while the number of pocket doses was added to the number of
MEMS openings. Estimates were calculated over a 28 day
interval. Unadjusted monthly MEMS adherence for the intermit-
tent group was calculated as the sum of days when volunteers were
adherent to fixed dosing (Mondays and Fridays with a MEMS
event, and non-Mondays and non-Fridays on which neither sexual
activity nor a MEMS event occurred) plus post-coital dosing (other
days on which sexual activity was reported by SMS and a MEMS
event occurred), divided by 28. In a post-hoc analysis, intermittent
dosing was adjusted for extra pills taken out of the MEMS bottle,
with all pills assigned to post-coital. Adherence was also assessed
by monthly self-report using timeline followback tools. Because
SMS response rates varied (see below), we also calculated
adherence to post-coital doses as the number of days with both
MEMS events and timeline followback reported sexual events
divided by the number of days with timeline followback reported
sexual events. Adherence for post-coital doses within 2 hours of
sex was calculated as the number of days post-coital dosing within
2 hours of sex by timeline followback report divided by the
number of days with sexual events per SMS. It was also calculated
as the number of days post-coital dosing within 2 hours of sex
occurred by timeline followback report divided by the number of
days sexual events occurred by timeline followback report.
Acceptability was assessed by Likert scale during the timeline
followback face-to-face assessment after 16 weeks in the study.
Volunteers with missing responses were excluded from the
Comparisons of categorical and continuous factors were
conducted using the Fisher’s exact test and Wilcoxon rank-sum
test, respectively. A two-sided p value of less than 0.05 was
considered to indicate statistical significance. Statistical analyses
were performed with the use of SAS software, version 9.2 (SAS
Institute, Cary, NC, USA).
Screening and clinical safety laboratories were performed on-
site following Good Clinical Laboratory Practices (GCLP) in labs
accredited by Qualogy UK . Interferon-c ELISpots were
performed on frozen peripheral blood mononuclear cells (PBMCs)
at KAVI and Kilifi laboratories on baseline and follow-up
specimens as described previously . A positive ELISpot was
defined as (1) an average background(mock)-subtracted count per
peptide greater than 38 spot forming units (SFU) per 106PBMCs
with the coefficient of variation no greater than 70%, (2) mean
count greater than 46 mean background (mock), and (3) mean
background (mock) below 50 SFU/106PBMCs.
A total of 107 volunteers were screened for eligibility and 72
volunteers, 67 men and 5 women, were randomized into the study
between October 19, 2009 and December 10, 2009. Enrollment of
women was limited in order to maintain a primarily MSM study
focus while avoiding community identification of the study as
MSM-exclusive. Laboratory abnormalities were the most common
reason for being excluded from participating, 22/35 (63%). The
most common laboratory abnormalities at baseline were creatinine
clearancecalculatedbytheCockcroft-Gault formula,80 mL/min,
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12/22 (55%) and proteinuria on urine dipstick, 4/22 (18%). Follow-
up continued until May 27, 2010, and 64 volunteers (89%)
completed the study (Figure 1). The trial stopped when the end of
the follow-up period was reached for all volunteers who completed
Baseline demographic and risk for HIV infection characteristics
were similar between groups (Table 1). Forty-seven percent of
volunteers reported drinking alcohol before sex, 67% reported
transactional sex and 64% reported having receptive anal sex in the
past 28 days. Volunteers in Kilifi were more likely to report using illicit
drugs than those in Nairobi (61% vs. 22%, p=0.022). All of the
cohort did not include women at the time of study initiation.
Analysis of safety, adherence, acceptability, and change in risk
behavior include all randomized volunteers who were HIV-1
negative at the time of randomization and for whom study
treatment was dispensed.
Outcomes and estimation
Ninety-seven percent of non-serious adverse events
(AEs) were mild or moderate, with 91% judged unlikely related or
not related to study drug. The proportion of volunteers with
moderate or above AEs did not differ by regimen (daily: 53%,
intermittent: 56%, p=1.00), or treatment groups (active: 60%,
placebo: 42%, p=0.14). The proportion with mild AEs was also
not different by regimen or treatment group (Table 2). The
percentage of volunteers with gastrointestinal complaints was not
significantly higher in active (42%) than placebo recipients (21%)
(p=0.12). Among those on the daily regimen, a total of 82 adverse
events (AEs) occurred; 91% were judged to be unlikely related or
unrelated to the study product; 96% were mild or moderate. A
similar pattern was observed among those on the intermittent
regimen with a total of 76 AEs of which 89% were unlikely related
or unrelated to the study product; 99% were mild or moderate.
Two volunteers had asymptomatic elevated plasma bilirubin levels
that were graded as very severe and unlikely related to study drug.
Two volunteers had a transient episode of neutropenia each that
was graded as severe and unlikely related to study drug. These AEs
resolved spontaneously. Mild creatinine elevations (1.1–1.3 times
Figure 1. Flow of participants.
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the upper limit of normal) were observed in three volunteers on
active regimen, all of which resolved spontaneously while
continuing study drug. Two cases of abnormal creatinine
clearance were detected, one in active and one in placebo
recipients, which resolved spontaneously. No other clinically
significant renal dysfunction was found. No drug-related SAEs
were reported. One HIV infection occurred in a volunteer in the
placebo group at week 16.
There was no difference in adherence rates
between treatment and placebo groups, thus these groups were
combined for the adherence analyses (Table 3). Median
unadjusted MEMS adherence rates were 83% [IQR: 63–92] for
daily dosing and 55% [IQR: 28–78] for fixed intermittent dosing
(p=0.003), while adherence to any post-coital doses was 26%
[IQR: 14–50]. Adherence rates did not change when adjusted for
curiosity openings (i.e. when no pills were taken out). When
adjusted for extra openings and extra pills taken out, median
MEMS adherence for daily dosing was 92% [IQR: 82–99]. In a
post-hoc analysis, intermittent dosing was adjusted for extra pills
taken out, as defined above, with all pills assigned to post-coital
dosing. Median MEMS adherence for post-coital dosing increased
to 88% [IQR: 50–152]. There was no difference by study site in
daily, fixed intermittent or post-coital dosing adherence rates. The
median number of days per week of PrEP use according to MEMS
data was 5.8 [IQR 4.4–6.4] in the daily group and 2.1 [IQR 1.3–
2.7] in the intermittent group.
SMS response rates and sexual activity.
were the primary measure of sexual activity used to calculate
overall intermittent dosing adherence and specifically post-coital
adherence. The median daily SMS response rate was 23% (range,
0–80), increasing to 33% (range, 0–100) when days with major
SMS server outages (.2 hour outage) are excluded. Major server
outages occurred on 65/316 (21%) days. Problems with SMS
Table 1. Baseline demographics and HIV risk behavior for the past 28 days by treatment assignment-schedule and study site.
Male gender – no. (%)21 (88) 24 (100) 11 (92) 11 (92)31 (86) 36 (100)67 (93)
Age – yr (mean
26 (20–36) 26 (19–35)27 (20–38) 28 (18–46)26 (18–36)27 (20–46)26 (18–46)
Drank alcohol before
sex – no. (%)
9 (38)14 (58) 5 (42)6 (50) 15 (42)19 (53)34 (47)
Used any street drugs –
8 (33) 10 (42)7 (58) 5 (42)22 (61) 8 (22)*30 (42)
Genital sore or
discharge – no. (%)
1 (4)0 (0) 0 (0)1 (8) 1 (3)1 (3) 2 (3)
Any condom use with
new male partners –
11 (85)11 (100) 5 (83)7 (100)19 (90)15 (94) 34 (92)
Any condom use with
new female partners –
5 (100)6 (100)4 (100)1 (100)7 (100)9 (100) 16 (100)
Gave or received money/
gifts for sex –
17 (74) 15 (63)8 (73)7 (58)26 (74)21 (60)47 (67)
Engaged in group
sex – no. (%)
1 (4)0 (0)0 (0) 0 (0)1 (3) 0 (0)1 (1)
Had receptive anal
sex – no. (%)
13 (59)17 (71) 5 (45)9 (75)19 (56)25 (71)44 (64)
Had insertive anal
sex – no. (%)
13 (65)14 (61)8 (80) 6 (55)18 (62)23 (66) 41 (64)
Number of sex partners
– median [IQR]
3 [2–4] 3 [2–4]3 [1.5–4.5] 3 [1.5–4]3 [1.5–4] 3 [2–4]3 [2–4]
Table 2. Number (percentage) of volunteers with AEs
categorized by maximum severity experienced, and treatment
assignment and schedule.
Maximum AE Severity
None MildMod Severe
Active Daily4 (17) 6 (25)11 (46)2 (8) 1 (4)
Intermittent 5 (21)4 (17) 14 (58)0 (0) 1 (4)
Overall9 (19)10 (21) 25 (52)2 (4) 2 (4)
PlaceboDaily 2 (17)5 (42) 5 (42)0 (0)0 (0)
Intermittent 4 (33)3 (25) 5 (42)0 (0)0 (0)
Overall6 (25) 8 (33)10 (42) 0 (0)0 (0)
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gateway providers required changing mobile phone networks and
SIM cards, and SMS responses decreased by over 60% among
volunteers who were requested to change SIM cards. Loss of
mobile phones was rare.
Because SMS response rates were low, we also calculated post-
coital adherence using timeline followback self-report data. The
median number of days per week when sex occurred by SMS
reporting was 1.4 [IQR: 0.4–2.5] in the daily group and 0.7 [IQR:
0.4–1.9] in the intermittent group. By timeline followback, it was
1.8 [IQR: 0.9–3.9] in the daily group and 1.0 [IQR: 0.7–1.6] in
the intermittent group. Using MEMS and timeline followback
sexual activity data, the median MEMS adherence rate for post-
coital dosing was 23% [IQR: 13–50]. Using timeline followback
adherence data and SMS sexual activity data, adherence for post-
coital doses within 2 hours of sex was 105% [IQR: 57–175]. Using
only timeline followback data for adherence and sexual activity
data, it was 100% [IQR: 96–100].
The most common reasons cited for missing a pill dose were
being away from home (12%), not having pills (11%), forgetting to
take pill (8%), a change in daily routine (7%), and using alcohol or
drugs (3%). There were no differences between daily and
intermittent groups in reasons for missing a pill dose.
Eighty-three percent (60/72) of volunteers
would be willing to use the pill regimen most or all of the time
if it was shown to be safe and effective and was inexpensive or free.
There was no difference in acceptability between daily and
intermittent groups (80% vs. 86%), or between active and placebo
groups (86% vs. 80%). Acceptability of using the MEMScap was
high with 88% (62/72) reporting it was somewhat or very easy to
use. Eleven volunteers required replacement of MEMS cap due to
loss or damage.
HIV behavior change.
The median number of sexual
partners in the past month increased from 3 [IQR 2–4] at
baseline to 4 [IQR 2–8] at month 4 during the trial, primarily due
to an increase of 3 [IQR 1.5–4] to 5 [IQR 2–12] at the Kilifi site.
Because there may have been underreporting of sex partners at
baseline, we also compared month 2 and month 4; the median
number of sexual partners was 4 at month 2 and at month 4. No
other HIV risk behaviors reported at baseline changed during the
HIV-specific immune responses.
immune responses were detected by IFN-c ELISpot at baseline;
two of 53 (3.8%) volunteers with specimens available for ELISpot
testing had a positive IFN-c ELISpot response at baseline, one to a
Nef peptide and one to all 6 peptide pools. Only four of 62 (6.5%)
volunteers with post-baseline ELISpot data had a response to one
or more peptides at a single time point. One volunteer assigned to
the intermittent active treatment group had positive IFN-c
ELISpot responses to a Pol/Int peptide during the study at week
12 and 16. Two volunteers in the intermittent active treatment
group responded to an Env peptide pool at week 16. One
volunteer in the intermittent placebo treatment group responded
to the RT peptide pool at week 16. The IFN-c ELISPOT
responses were generally low magnitude.
Interpretation and Overall Outcome
To our knowledge, this is the first report of safety and adherence
to an intermittent PrEP regimen. It describes the use of both daily
and intermittent PrEP regimens in a primarily MSM population in
sub-Saharan Africa, which is a key risk group that may be targeted
for PrEP. In addition, this is the first published report of the use of
electronic medication monitoring for PrEP adherence. Safety with
FTC/TDF for PrEP was similar for both daily and intermittent
users. Similar to the larger iPrEX study using FTC/TDF, the
Partners PrEP trial using FTC/TDF and TDF, and the Botswana
TDF2 trial using FTC/TDF, we found no significant drug safety
patterns [3, Baeten 2011, Thigpen 2011]. Our study adds to the
safety data on FTC/TDF PrEP for African men with 48
volunteers in the active treatment group, compared to 45 African
men on active treatment in the iPrEX study. However our safety
data reflects only short-term use over a four month period, with
varying levels of adherence among volunteers. Like the iPrEX
study, a higher proportion of volunteers in the active treatment
group had gastrointestinal complaints, but this was not statistically
Table 3. PrEP adherence rates for daily and intermittent groups.
DAILY ADHERENCE RATEOverall unadjusted 82% [62–89] 84% [63–96]83% [63–92]
Adjusted* 92% [79–101]93% [84–96]92% [82–99]
Overall unadjusted72% [62–80]68% [63–76] 68% [63–78]
Fixed doses56% [31–88] 34% [19–72]55% [28–78]
Post-coital doses32% [13–50]19% [14–45] 26% [14–50]
Post-coital doses – (MEMS events
and self report sexual events)
27% [13–60]16% [8–37]23% [13–50]
Post-coital doses within
2 hrs** (self report and sexual
events per SMS)
115% [57–175]100% [61–174]105% [57–175]
Post-coital doses within
2 hr (self report doses and
100% [100–100]100% [67–100]100% [96–100]
*Adjusted accounts for extra openings and extra pills taken out.
**Days on which sexual event reported per SMS.
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significant. No evidence of renal dysfunction was found.
Acceptability of PrEP was high, and interestingly, did not differ
between daily and intermittent users.
Median adherence as measured by MEMS was significantly
higher for daily use, 83%, compared to either component of the
intermittent regimen, either the fixed Monday and Friday doses,
55%, or the post-coital doses, 26%. After adjusting the daily
adherence measurement for extra pills taken out, median
adherence to daily dosing may have been as high as 92%. The
unadjusted median adherence for daily use fell in between self-
reported or clinic-based pill count measures of adherence in the
iPrEx study, 95% and 89–95% respectively, and clinic-based pill
count in the West African study, 74%. However, both self-report
and clinic-based pill count have been shown to be inaccurate
measures of adherence in many settings, typically overestimating
adherence compared to electronic monitoring, unannounced
home-based pill counts, and random drug levels [27–29]. In
contrast, preliminary data from a PrEP study in HIV discordant
heterosexual couples in East Africa found near perfect adherence
rates by multiple measures, 99.1–101.9% by MEMS, unan-
nounced home-based pill counts or clinic-based pill counts.
(Haberer J, Baeten J, Celum C, Tumwesigye E, Katabira E et
al. (2011) Near Perfect Early Adherence to Antiretroviral PrEP
against HIV Infection among HIV Serodiscordant Couples as
Determined by Multiple Measures: Preliminary Data from the
Partners PrEP Study [Abstract 488]. In: Proceedings of the 18th
Conference on Retroviruses and Opportunistic Infections; 27
February–2 March 2011; Boston, Massachusetts, United States.
CROI 2011. Available: http://www.retroconference.org/2011/
Abstracts/41269.htm. Accessed 14 March 2012.) This high level
of adherence may be due to providing PrEP in the context of
stable, socially supported relationships as well as the uninfected
partner’s hope of maintaining good health while at the same time
preserving their serodiscordant relationship . These factors are
less likely to play a role in the primarily MSM population in our
The lower rates of adherence to fixed and post-coital dosing
may be due to either true lower adherence to these dosing
schedules, or inaccurate measurement for these regimens using
MEMS and SMS reporting. Volunteers were allowed to take extra
doses out of the MEMS bottle, for use during travel and/or for
post-coital dosing away from home, and even encouraged to do so
by distribution of key-chain pill holders. Therefore, it was difficult
to know whether self-reported extra pills taken out should be
assigned to fixed doses or post-coital doses. However, if all self-
reported extra pills taken out were assigned to post-coital dosing,
median adherence for post-coital dosing increased from 26% to
88%, suggesting that lower rates of adherence to post-coital dosing
may be due in part to inaccurate measurement of this type of
dosing with MEMS reporting. However, assessment of adherence
to an intermittent regimen including post-coital doses requires self-
report measurement of sexual activity, which is known to be
inaccurate [31,32] We used daily SMS reporting of sexual activity
as the primary measure with that hope that frequent measure-
ments would decrease recall bias. However SMS response rates
varied due to technical and behavioral reasons and overall were
low. By substituting timeline followback report of sexual activity
for SMS data, median post-coital adherence rate did not improve,
26%, since self-reported sexual activity was low by both measures.
However, using exclusively timeline followback self-report data for
both adherence and sexual activity, median post-coital dosing
adherence was 100%, as was median adherence to post-coital
dosing within 2 hours of sex, 100%. These perfect adherence rates
suggest that self-report overestimated both pill-taking and sexual
activity in this study. Our data highlights the difficulty of
measuring adherence to a coitally-dependent regimen. Novel
measures providing more accurate data on sexual behavior are
needed to improve our assessment and understanding of this type
of intermittent dosing. In addition, qualitative data could provide
deeper insight into barriers to coitally-dependent PrEP.
Volunteers in daily and intermittent groups reported a median
1.4 and 0.7 sex acts per week by SMS, respectively, and a median
4 sex partners per month by timeline followback self-report, which
appears lower than what has been measured previously in at least
one of these cohorts. In a comparison study of interview methods
at cohort enrolment of MSM and FSW in Kilifi, audio computer-
assisted self-interview (ACASI) captured double the median
number of regular and casual partners per week compared to
face-to-face interview (2 vs. 1) . In a prospective diary study of
MSM in the Kilifi cohort, we found high rates of sexual activity:
83 volunteers reported having a median 2.5 sex partners per week
and 3.6 sex acts per week (Smith AD, Ferguson A, Kowour D,
Van Der Elst E, Agwanda C, et al. (2009) Role Versatility and
Female Partnerships among Men Who Sell Sex to Men:
Mombasa, Kenya [Abstract 1029]. In: Proceedings of the 16th
Conference on Retroviruses and Opportunistic Infections; 8–11
February 2009; Montreal, Canada. CROI 2009. Available:
cessed 14 March 2012.) The apparent under-reporting of sexual
activity in this study may be due to various causes, including a
preference to remember behaviors that occurred on days that pills
were taken, unfamiliarity with daily reporting of sexual behavior
through SMS, and technical difficulties with SMS.
Lower adherence to intermittent fixed and post-coital dosing
may have been due to several barriers. Daily pill-taking behavior is
more routine and may be easier to remember than fixed
intermittent, twice weekly doses. Few published studies address
adherence to less than daily medication regimens, even in the
tuberculosis field, where intermittent dosing regimens are
common. Changes in routine due to illness, travel or family
obligations have been correlated with adherence difficulties with
daily regimens; these factors are likely to impact intermittent
regimens as well . Perceived HIV risk may influence
adherence. If perceived HIV risk is low on the assigned days,
adherence may be lower, whereas daily pill adherence may involve
less frequent consideration of perceived HIV risk. Perceived HIV
risk may influence post-coital adherence depending on the
serostatus of the recent sexual partner if known, whether the
encounter was anal insertive or receptive, protected or unprotect-
ed by condoms, and whether the partner was known or
anonymous. Perceived HIV risk has been associated with
partner-specific differences in condom use, which, although less
covert, is a reasonable comparison for post-coital PrEP [35–37].
Close to half of volunteers reported using alcohol before sex. Such
substance use around the time of sex could reduce adherence to
post-coital dosing. Alcohol use was reported as a barrier to
acyclovir adherence in another herpes suppression trial in Africa
. In addition, stigma of disclosing HIV at-risk status by taking
medication in the presence of a partner may reduce post-coital
adherence. Due to the relatively high frequency of transactional
sex in this population, volunteers may travel for sex and may not
have pills with them at the time for post-coital dosing. It is not
clear whether pre-coital dosing would be more successful than
post-coital dosing. Pre-coital dosing may still be hampered by
travel and location issues as well as drug impairment. Allowing a
longer window, e.g. morning dosing on the day of sex, might avoid
these issues, but predicting the likelihood of sexual activity later in
the day may be unreliable.
Intermittent PrEP in African MSM
PLoS ONE | www.plosone.org7 April 2012 | Volume 7 | Issue 4 | e33103
Our findings suggest that adherence to intermittent dosing
regimens, fixed doses and in particular coitally-dependent doses,
may be more difficult than adherence to daily dosing. However,
intermittent dosing may still be appropriate for PrEP if
intracellular drug levels, which correlate with prevention of HIV
acquisition, can be attained with less than daily dosing and if
barriers to adherence can be addressed. Forthcoming data from
the present study will analyze plasma and intracellular drug levels
in both the daily and intermittent groups to determine median
drug levels attained at different strata of adherence. Data from
ongoing directly observed dosing studies  and PrEP efficacy
trials [40,41] may provide sufficient information to determine
what intracellular drug levels can be achieved with intermittent
dosing and to define the minimum protective drug concentration.
Therefore data on drug levels may be key to establishing what
level and pattern of adherence is necessary for PrEP effectiveness.
If twice weekly dosing of FTC/TDF can produce intracellular
drug levels that correlate with efficacy, then this regimen may be
appropriate for PrEP if the adherence rate can be improved from
the median 55% found for twice weekly fixed dosing in this
Despite encouraging data from animal studies, we found no
evidence of HIV-specific immune responses as measured by a
validated IFN-c ELISpot in volunteers on PrEP. It is possible that
a longer duration of PrEP and/or more intensive mucosal
exposures are necessary to develop these responses, or that too
few volunteers were exposed to HIV in this trial. Alternatively, if
PrEP-related protective responses do exist, they may be located in
the mucosa and may not be evaluable with T-cell assays in PBMCs
such as IFN-c ELISpots.
Our findings on PrEP safety, acceptability and adherence in
African MSM may be applicable to MSM in other settings,
particularly in the developing world and in groups with high rates
of transactional sex and alcohol use. However our study has
several limitations. Only a small number of women participated in
the study, limiting generalization of results to this population.
Sixty-three percent of ineligible volunteers were excluded for lab
abnormalities, with decreased creatinine clearance and proteinuria
accounting for 85% of these exclusions. We used a conservative
creatinine clearance cut-off of ,80 mL/min, which may account
in part for the relatively high rate of lab-based exclusions in our
study. However the percentage of all screened volunteers who
were excluded due to decreased creatinine clearance was only
11%, which should not diminish the generalizability of the results.
The duration of follow-up was short and may not reflect safety and
adherence outcomes for longer-term use of PrEP. Some volunteers
likely had low levels of drug exposure, particularly in the
intermittent group, where the median number of days per week
of PrEP use was 2.1 [IQR 1.3–2.7]. However, safety outcomes
were similar for the intermittent and daily groups, and reflected
findings of larger PrEP studies with longer durations of exposure.
Volunteers were recruited from existing HIV prevention cohorts
in which volunteers received ongoing HIV risk reduction
counseling and preventive services, so their behavior may not
reflect the larger population at risk for HIV. Although the majority
of volunteers had mobile phones and used SMS messaging prior to
enrollment, none had experience responding to daily SMS
messages for research purposes, particularly questions about
sexual activity. It is possible that SMS response rates would be
higher once technical outages had been resolved and volunteers
had additional familiarity with this technology in a research
Our data suggest that although adherence is lower than with
daily regimens, intermittent PrEP dosing with a fixed regimen in
this at-risk population is feasible. Additional drug level data,
qualitative data on adherence barriers, and better methods to
measure sexual activity are necessary to determine whether
adherence to post-coital PrEP could be comparable to more
standard regimens. Larger studies of intermittent PrEP with longer
follow-up in additional at-risk populations can examine whether
fixed intermittent PrEP regimens can achieve drug levels
comparable to the minimum effective concentration which may
be determined by ongoing efficacy trials. Alternate approaches to
peri-coital dosing might be more successful. Additional work on
using SMS to assess sexual activity may be warranted.
We would like to acknowledge the contributions of the study volunteers to
this research. We would like to thank the research center staff in Kilifi and
Nairobi. Lorna Clark conducted and Josephine Cox oversaw the IFN-c
ELISpot analyses at the IAVI Human Immunology Laboratory. This
paper was published with permission from the Director of KEMRI.
Conceived and designed the experiments: FP PF ES GM JFR DB.
Performed the experiments: GM ES PM OA PC DM. Analyzed the data:
BB FP ES GM JH. Contributed reagents/materials/analysis tools: JFR.
Wrote the paper: FP ES GM PM JH DB BB JFR PF.
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