Annals of Internal Medicine
Daily Oral Tenofovir and Emtricitabine–Tenofovir Preexposure
Prophylaxis Reduces Herpes Simplex Virus Type 2 Acquisition
Among Heterosexual HIV-1–Uninfected Men and Women
A Subgroup Analysis of a Randomized Trial
Connie Celum, MD, MPH; Rhoda A. Morrow, PhD; Deborah Donnell, PhD; Ting Hong, MD, PhD; Craig W. Hendrix, MD, PhD;
Katherine K. Thomas, MS; Kenneth H. Fife, MD, PhD; Edith Nakku-Joloba, MBChB, PhD; Andrew Mujugira, MBChB, MPH; and
Jared M. Baeten, MD, PhD, for the Partners PrEP Study Team*
Background: Daily oral preexposure prophylaxis (PrEP) using the
antiretroviral tenofovir disoproxil fumarate (TDF) alone or in com-
bination with emtricitabine (FTC–TDF) reduces the risk for HIV-1
acquisition. Tenofovir has in vitro activity against herpes simplex
virus type 2 (HSV-2).
Objective: To assess the efficacy of daily oral PrEP with tenofovir
and FTC–TDF in the prevention of HSV-2 acquisition.
Design: Subgroup analysis of data from a randomized, placebo-
controlled trial with concealed allocation. (ClinicalTrials.gov:
NCT00557245)
Setting: Multiple sites in Kenya and Uganda.
Participants: Heterosexual men and women who were seronega-
tive for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due
to having an HIV-1–infected partner.
Intervention: Once-daily oral tenofovir disoproxil fumarate (TDF),
alone or combined with emtricitabine (FTC-TDF), compared with
placebo.
Measurements: HSV-2 seroconversion.
Results: A total of 131 participants seroconverted to HSV-2 (79 of
1041 assigned to tenofovir or FTC–TDF PrEP [HSV-2 incidence, 5.6
P reexposure prophylaxis (PrEP) with the oral antiretro-
viral tenofovir disoproxil fumarate (TDF) alone or in
combination with emtricitabine (FTC–TDF) has been
shown to significantly reduce the risk for HIV-1 acquisi-
tion in 4 randomized, placebo-controlled clinical trials in
high-risk populations (1– 4). In addition to its potent ac-
tivity as a nucleotide inhibitor of HIV-1 reverse transcrip-
tase, tenofovir has anti– herpes simplex virus type 2
(HSV-2) activity in vitro, although less than the related
compounds cidofovir and adefovir (5). In a randomized
trial of pericoital dosing of intravaginal 1% tenofovir gel,
HSV-2 incidence was reduced by 51% compared with pla-
cebo (6 – 8) and vaginal tenofovir levels were associated
with protection against HIV-1 and HSV-2 (9). These re-
sults were consistent with in vitro studies showing antiher-
petic activity against HSV-2 isolates at concentrations of
10 to 200 ␮g/mL (10), levels that are in the range of those
achieved with vaginal dosing of tenofovir gel (11). How-
ever, whether tenofovir concentrations achieved through
oral dosing are sufficient for HSV-2 protection in humans
is unknown.
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Original Research
per 100 person-years] and 52 of 481 assigned to placebo [HSV-2
incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for
HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to
0.99; P ⫽ 0.047) compared with placebo, and the absolute risk
reduction was 2.1 per 100 person-years. Among the 1044 partic-
ipants with HSV-2–infected partners, the HR for PrEP was 0.67 (CI,
0.46 to 0.98; P ⫽ 0.038) compared with placebo, and the absolute
risk reduction was 3.1 per 100 person-years.
Limitation: Randomization was not stratified by HSV-2 status, and
diagnostic tests to exclude participants with acute HSV-2 at base-
line are not available.
Conclusion: Daily oral tenofovir-based PrEP significantly reduced
the risk for HSV-2 acquisition among heterosexual men and
women. Modest protection against HSV-2 is an added benefit of
HIV-1 prevention with oral tenofovir-based PrEP.
Primary Funding Source: Bill & Melinda Gates Foundation.
Ann Intern Med. 2014;161:11-19. doi:10.7326/M13-2471 www.annals.org
For author affiliations, see end of text.
* For a list of the members of the Partners PrEP Study Team, see the
Appendix (available at www.annals.org).
The efficacy of daily oral tenofovir-based PrEP for
HSV-2 protection has not been assessed in heterosexual
populations. In vitro data have shown that high concentra-
tions of tenofovir are required for HSV-2 inhibition, and
high adherence to oral PrEP may be necessary to achieve
such levels. We performed a secondary analysis of HSV-2
acquisition among participants who were initially seroneg-
ative for HIV-1 and HSV-2 in a randomized trial of PrEP
for HIV-1 prevention that showed high efficacy for HIV-1
protection (2).
METHODS
Study Population and Procedures
Between July 2008 and November 2010, a total of
4747 heterosexual HIV-1–serodiscordant couples were en-
rolled in a randomized trial of PrEP for HIV-1 prevention
(the Partners PrEP Study) and followed at 9 research sites
in Kenya and Uganda (2, 12). The primary aims of the
study were to determine the efficacy and safety of PrEP
with tenofovir and FTC–TDF, each compared with pla-
© 2014 American College of Physicians 11
 Original Research HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis
Context
Herpes simplex virus type 2 (HSV-2) infection is common
worldwide, can lead to complications, and has been asso-
ciated with an increased risk for HIV-1 infection.
Contribution
In a secondary analysis of a large randomized clinical trial
testing the ability of tenofovir-based preexposure regimens
to prevent HIV-1 infection, participants receiving tenofovir
were less likely to acquire HSV-2 than those receiving
placebo.
Caution
The trial was not originally designed to study HSV-2
acquisition.
Implication
Protection against HSV-2 acquisition may be an added
benefit of using tenofovir for HIV-1 preexposure
prophylaxis.
—The Editors
cebo, for prevention of HIV-1 acquisition. Eligibility cri-
teria for HIV-1–seronegative partners included normal re-
nal function and not being pregnant or breastfeeding. At
enrollment, HIV-1–seronegative partners were assigned in
a 1:1:1 ratio to once-daily oral tenofovir, FTC–TDF, or
placebo; investigators and participants were blinded to
randomization assignments. Randomization was by fixed-
size blocks and was stratified by site but not by HSV-2
serostatus. Participants who were HIV-1–seronegative had
monthly visits for up to 36 months that included HIV-1
testing, dispensation of study medication, and standardized
assessment of sexual behavior and clinical and laboratory
safety. Study medication was withheld from women who
became pregnant or began breastfeeding. All participants
received a comprehensive package of HIV-1 prevention
services, including individual and couples risk-reduction
counseling, screening for and treatment of sexually trans-
mitted infections, condoms, and referral for medical male
circumcision and postexposure prophylaxis according to
national policies. Partners infected with HIV-1 were not
eligible for antiretroviral therapy (ART) under the national
policies of Kenya and Uganda at the time of their enroll-
ment in the trial; they were followed in parallel with their
HIV-1– uninfected partners and referred for initiation of
ART when they became eligible. Participants with HIV-1
seroconversion were referred for care, but the standard of
care in Kenya and Uganda is to not treat acute HIV-1
infection, although clinical teams referred pregnant women
with acute HIV-1 infection for prompt ART initiation. At
an interim review in July 2011, the trial’s independent data
and safety monitoring board recommended that the pla-
cebo group be discontinued early because of clear demon-
stration of PrEP efficacy for HIV-1 prevention (2).
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A secondary analysis of HSV-2 protection from oral
tenofovir-based PrEP compared with placebo was planned
after July 2010, when a randomized trial of pericoital dos-
ing of 1% tenofovir gel showed efficacy against HSV-2
acquisition (6 – 8). This finding was not anticipated in the
original design of trials of tenofovir-based PrEP but could
be assessed among the subset of participants who were
HSV-2– uninfected at baseline. All HSV-2 testing and de-
termination of end points was concluded before unblind-
ing of HSV-2 outcomes. To correspond with the period
covered in the primary HIV-1 acquisition results from the
trial, we included data through July 2011 in our analysis of
HSV-2 acquisition. Because the objective of this secondary
analysis of HSV-2 prevention was to determine the effect
of daily oral tenofovir on HSV-2 incidence, this report
includes data only on participants who did not have
HSV-2 infection at baseline (Figure 1).
The study protocol was approved by the University
of Washington Human Subjects Review Committee and
ethics review committees at each of the study sites. All
participants provided written informed consent in English
or their local language.
Laboratory Procedures
HSV-2 Serologic Tests
For HIV-1– uninfected partners, we tested archived
baseline sera for HSV-2 antibodies by using an HSV-2–
specific enzyme immunoassay (EIA) (Focus Technologies,
Cypress, California). On the basis of previous experience
with this EIA in East Africa (13), index value results less
than 0.9 were considered to represent HSV-2– uninfected
status, values of 3.5 or greater signified HSV-2–infected
status, and values of 0.9 to 3.4 were considered indetermi-
nate. We used HSV-2–specific Western blot to clarify in-
determinate results (14). For participants determined to be
HSV-2–seronegative at baseline, serostatus at the final visit
through July 2011 was then assessed with an HSV-2–
specific EIA and Western blot using the same approach as
for baseline samples. Finally, individuals found to have
seroconverted to HSV-2 between baseline and their final
follow-up visit had sera from study months 1, 3, 6, 12, 18,
24, 30, and 36 tested in batch by HSV-2–specific Western
blot to determine the timing of seroconversion. An HSV-2
end point committee reviewed the serologic data in a
blinded manner to adjudicate end points.
We tested HSV-2 serostatus at baseline for the HIV-1–
infected partners of HSV-2–seronegative participants. In-
dex EIA values less than 0.9 signified HSV-2– uninfected
status, values of 3.5 or greater signified HSV-2–infected
status, and HSV-2–specific Western blot was used to con-
firm the status of EIA values between 0.9 and 3.4. We did
not conduct longitudinal testing among HIV-1–infected
partners who were HSV-2–seronegative because of the
high baseline prevalence of HSV-2.
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 HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis Original Research

Figure 1. Study flow diagram.

Eligible couples randomly assigned (n = 4747)

Randomly assigned to TDF Randomly assigned to FTC–TDF Randomly assigned to placebo

(n = 1584) (n = 1579) (n = 1584)

Excluded (n = 1071) Excluded (n = 1051) Excluded (n = 1103)

HSV-2–positive: 973 HSV-2–positive: 964 HSV-2–positive: 1012
Indeterminate HSV-2 status: 56 Indeterminate HSV-2 status: 56 Indeterminate HSV-2 status: 55
Missing result: 42 Missing result: 31 Missing result: 36

HSV-2–negative at enrollment HSV-2–negative at enrollment HSV-2–negative at enrollment

(n = 513) (n = 528) (n = 481)

Retention Retention Retention

6 mo: 495/511 (96.9%) 6 mo: 501/525 (95.4%) 6 mo: 463/479 (96.7%)
12 mo: 396/425 (93.2%) 12 mo: 420/453 (92.7%) 12 mo: 399/422 (94.6%)
24 mo: 199/219 (90.9%) 24 mo: 214/233 (91.9%) 24 mo: 207/224 (92.4%)
36 mo: 2/2 (100%) 36 mo: 3/3 (100%) 36 mo: 2/2 (100%)

No follow-up (n = 8)
No follow-up (n = 7) Indeterminate HSV-2 status at No follow-up (n = 8)
last visit (n = 1)

Analyzed (n = 506) Analyzed (n = 519) Analyzed (n = 473)

HSV-2–positive: 42 HSV-2–positive: 37 HSV-2–positive: 52 Analytic
HSV-2–negative: 464 HSV-2–negative: 482 HSV-2–negative: 421 sample

Retention of partners who were seronegative for HIV-1 and HSV-2 was calculated as cumulative retention, which was defined as remaining in follow-up
and having available HSV-2 serostatus information. A total of 131 participants seroconverted to HSV-2 (42 in the tenofovir group, 37 in the FTC–TDF
group, and 52 in the placebo group) and were included in the intention-to-treat analysis. FTC–TDF ⫽ emtricitabine in combination with tenofovir
disoproxil fumarate; HSV-2 ⫽ herpes simplex virus type 2; TDF ⫽ tenofovir disoproxil fumarate.

Plasma Tenofovir Levels Statistical Analysis

We used a case– cohort design to select a random sam-
ple of participants from the active PrEP groups for assess-
ment of plasma concentrations of tenofovir. Case partici-
pants were those with HSV-2 seroconversion in the active
PrEP groups, and control participants were a random sam-
ple (selected in a 2:1 ratio compared with case participants)
who were assigned to active PrEP and did not acquire
HSV-2. We assessed plasma tenofovir levels in case and
control participants at 1, 3, 6, 12, 18, 24, 30, and 36
months after enrollment, thus including testing at the visits
at which HSV-2 seroconversion was detected for case par-
ticipants. Plasma tenofovir concentrations were determined
by previously described liquid chromatography–mass spec-
trometry methods (15).
Plasma HIV-1 RNA Levels and CD4 Cell Counts in
HIV-1–Infected Partners
We quantified CD4 cell counts by using standard flow
cytometry and plasma HIV-1 RNA levels by using the
COBAS AmpliPrep/COBAS TaqMan real-time HIV-1
RNA assay, version 1.0 (Roche Diagnostics, Indianapolis,
Indiana), with a lower limit of quantification of 240
copies/mL.
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The primary outcome was HSV-2 seroconversion
among persons who were HSV-2–seronegative at baseline,
and the primary analysis was intention-to-treat. The only
exception was that participants who acquired HIV-1 were
censored after the first visit at which they were HIV-1–
seropositive because the study drug was withheld at that
time. Thus, those with HIV-1 seroconversion contributed
follow-up time for assessment of HSV-2 up to and includ-
ing the visit when HSV-2 seroconversion or HIV-1 sero-
conversion was detected, whichever occurred first. We
compared both active PrEP groups (FTC–TDF and teno-
fovir combined) with the placebo group given that teno-
fovir was the common active moiety against HSV-2 in
both groups and emtricitabine is not known to have activ-
ity against HSV-2 (16). Assessment of HSV-2 was interval-
censored at the specified study visits, so discrete time pro-
portional hazards models were used to estimate hazard
ratios (HRs) for HSV-2 infection (17). We fit these models
using the PROC LOGISTIC statement in SAS, version
9.3 (SAS Institute, Cary, North Carolina), with a comple-
mentary log-log link, including visit interval as a class vari-
able without an intercept term, in addition to the covariate
of interest (treatment group). The proportional hazards as-
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 Original Research HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis
sumption was tested by including interactions between
visit and treatment group. In a sensitivity analysis, we also
stratified the proportional hazards model by site. Prespeci-
fied subgroup analyses were performed to explore the uni-
formity of treatment effects found in the overall analysis.
These included baseline covariates of sex of HIV-1–
uninfected partners; circumcision status of HIV-1–
uninfected male participants; and plasma HIV-1 RNA
level (ⱖ50 000 vs. ⬍50 000 copies/mL), CD4 count
(⬍0.350 vs. ⱖ0.350 ⫻ 109 cells/L), and HSV-2 serostatus
of HIV-1–infected partners.
In addition to the primary proportional hazards anal-
ysis, we conducted sensitivity analyses to examine the po-
tential effect of confounding and bias that could have re-
sulted from using the subset of the HSV-2– uninfected
cohort from the randomized trial, loss to follow-up, and
censoring of participants with HIV-1 seroconversion. A
marginal structural model approach was used, adjusted for
age, sex, unprotected sex at baseline, and weighting that
accounted for time-dependent unprotected sex during
follow-up. Logistic regression was used to estimate stabi-
lized inverse weights (18), which were used to conduct an
adjusted, weighted discrete proportional hazards analysis
using the procedure described earlier. In a separate sensi-
tivity analysis to assess the potential effects of early censor-
ing of participants who acquired HIV-1, we conducted
simulation modeling to estimate the HR if these partici-
pants had continued in follow-up at the observed HSV-2
risk and at higher risk.
We performed a case– cohort analysis of plasma teno-
fovir concentrations to assess the risk for HSV-2 acquisi-
tion associated with detection (⬎0.3 ng/mL) versus non-
detection, using the same approach as in the case– cohort
analysis of plasma tenofovir concentrations and HIV-1
protection in the Partners PrEP Study (2). The case–
cohort analysis was performed using drug concentrations
in all selected participants, regardless of drug holds in the
prior interval (for example, for pregnancy or clinical
events). We used case– cohort methods in a Cox propor-
tional hazards model to estimate the HR of infection for
detectable versus undetectable tenofovir in plasma (19). In
this nonrandomized comparison, the model was adjusted
for factors that might be associated with adherence to the
study drug, including age, polygamous marriage, and un-
protected sex as a time-dependent variable (20). This anal-
ysis used the 2-phase design approach to the case– cohort
analysis (21).
All analyses were conducted using SAS, version 9.3,
with the exception of the case– cohort analysis, for which
we used R, version 3.0.0 (survey package 3.28-2 and
Hmisc package 3.10-1.1, R Foundation for Statistical
Computing, Vienna, Austria).
Role of the Funding Source
The Bill & Melinda Gates Foundation funded the
study but did not oversee the protocol. Gilead Sciences
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donated the study medication but had no role in data col-
lection or analysis.
RESULTS
Of the 4747 HIV-1– uninfected partners enrolled in
the trial, 4638 (97.7%) had baseline samples available for
HSV-2 testing; of these, 1522 (32.8%) were HSV-2–
seronegative (Figure 1), of whom 1498 (98.4%) had a final
study visit sample for HSV-2 testing. The median age of
the initially HSV-2–seronegative participants was 31 years,
and 80% were men, 40% of whom were uncircumcised. At
enrollment, 96% were married to their HIV-1–infected
partner, 8% reported an outside partner, the median num-
ber of sex acts in the prior month was 4, and 27% reported
unprotected sex (Table 1). A total of 237 HIV-1–infected
partners (15.6%) initiated ART during follow-up; 25
(1.6% of all HIV-1–infected partners) reported receiving a
tenofovir-containing regimen.
Follow-up and Adherence
Retention was greater than 90% for all groups during
the study period (Figure 1), with a median follow-up of 18
months (interquartile range, 12 to 24 months; range, 0 to
36 months). Study medication was dispensed at 96% of
attended visits. The most common reason for withholding
study medication was pregnancy, which did not differ sig-
nificantly by study group and accounted for 1.5% of
follow-up time. Study medication interruptions due to
safety-related reasons accounted for 0.5% of follow-up
time.
The primary measure of adherence was monthly pill
counts of returned study tablets. Ninety-eight percent of
dispensed study bottles were returned, and pill counts in-
dicated that 96% of dispensed tablets were taken. When
missed visits, other reasons for nondispensation of study
medication, and nonadherence to dispensed study pills
were taken into account, 90.9% of follow-up time for this
analysis was covered by study medication.
HSV-2 Incidence by Group
A total of 131 participants had incident HSV-2 infec-
tion (79 in the active PrEP groups [incidence, 5.6 per 100
person-years] and 52 in the placebo group [incidence, 7.7
per 100 person-years]) (Table 2). The HR for HSV-2 ac-
quisition with PrEP compared with placebo was 0.70
(95% CI, 0.49 to 0.99; P ⫽ 0.047) (Figure 2), and the
absolute risk reduction was 2.1 per 100 person-years.
When the 2 PrEP groups were considered separately, 42
HSV-2 infections were observed among participants as-
signed tenofovir (incidence, 6.1 per 100 person-years) and
37 were seen among those assigned FTC–TDF (incidence,
5.1 per 100 person-years), indicating an HR for HSV-2
acquisition of 0.76 (CI, 0.51 to 1.14; P ⫽ 0.186) for teno-
fovir and 0.64 (CI, 0.42 to 0.98; P ⫽ 0.041) for FTC–
TDF, each compared with placebo. The causal effect of
PrEP, which we estimated using marginal structural mod-
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 HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis Original Research

Table 1. Baseline Characteristics of Participants Who Were Dually Seronegative for HIV-1 and HSV-2

Variable Tenofovir FTC–TDF Placebo Total

(n ⴝ 513) (n ⴝ 528) (n ⴝ 481) (n ⴝ 1522)
Demographic characteristics
Men n (%) 408 (80) 422 (80) 389 (81) 1219 (80)
Median age (IQR), y 30 (26–36) 30 (26–36) 31 (26–36) 31 (26–36)
Median education (IQR), y 8 (5–12) 8 (5–11) 8 (5–11) 8 (5–11)
Any monthly income, n (%) 435 (85) 433 (82) 398 (83) 1266 (83)

Couple characteristics
Married to study partner, n (%) 489 (95) 506 (96) 466 (97) 1461 (96)
Median time living with study partner (IQR), y 4.7 (1.5–10.0) 5.0 (2.0–11.0) 4.5 (1.6–10.0) 5.0 (1.6–10.0)

Sexual risk behavior

Median sex acts in prior month (IQR), n 4 (3–8) 4 (3–8) 4 (3–9) 4 (3–8)
Any unprotected sex acts in prior month, n (%) 150 (29) 145 (27) 113 (23) 408 (27)
Any sex with outside partner in prior month, n (%) 48 (9) 39 (7) 36 (7) 123 (8)

Clinical characteristics of HIV-1–seronegative partner

Median CD4 count (IQR), ⫻ 109 cells/L 0.481 (0.366–0.680) 0.493 (0.387–0.680) 0.519 (0.395–0.677) 0.496 (0.382–0.680)
Median plasma HIV-1 RNA level (IQR), log10 copies/mL* 3.8 (3.1–4.3) 3.7 (3.0–4.4) 3.9 (3.2–4.5) 3.8 (3.1–4.4)

Clinical characteristics of HIV-1/HSV-2–seronegative participant, n (%)

Uncircumcised (men only) 162 (40) 177 (42) 150 (39) 489 (40)
Curable sexually transmitted infection† 26 (5) 19 (4) 35 (7) 80 (5)

FTC–TDF ⫽ emtricitabine in combination with tenofovir disoproxil fumarate; HSV-2 ⫽ herpes simplex virus type 2; IQR ⫽ interquartile range.
* Data were not available for 16 HIV-1–infected partners.
† Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis detected by nucleic acid amplification testing. Data were not available for 14 participants.

eling, was essentially the same as the result from the pro-
portional hazards model (HR, 0.69 [CI, 0.49 to 0.99];
P ⫽ 0.041). The magnitude of reduction in incident
HSV-2 in the PrEP groups compared with placebo was
similar in subgroup categories, including men and women,
circumcised and uncircumcised HIV-1–infected men, and
individuals whose HIV-1–infected partners had higher or
lower plasma HIV-1 RNA levels. However, PrEP was more
effective in reducing HSV-2 acquisition among individuals
whose HIV-1–infected partner had a baseline CD4 count
of at least 0.350 ⫻ 109 cells/L than among those whose
partner had a CD4 count below this level.
Baseline HSV-2 serostatus was available for 1493
HIV-1–infected partners, of whom 1044 (69.9%) were
HSV-2–seropositive. For HIV-1– uninfected persons with
a partner co-infected with HIV-1 and HSV-2, incidence of
HSV-2 was 10.1 per 100 person-years in the placebo group
and 7.0 per 100 person-years in the PrEP groups (HR,
0.67 [CI, 0.46 to 0.98]; P ⫽ 0.038). Participants whose
HIV-1–infected partners were HSV-2–seronegative could
have acquired HSV-2 from outside partners; among the 13
such participants with incident HSV-2 infection, none re-
ported outside partners at study enrollment, but 6 reported
an outside partner during follow-up (5 of the HIV-1–
uninfected partners and 1 of the HIV-1–infected partners).
Twenty-three participants seroconverted to HIV-1; of
these, 5 seroconverted to HSV-2 before HIV-1 and 18 (11
in the placebo group and 7 in the PrEP groups) were HSV-2–
seronegative at the last visit before HIV-1 seroconversion.
A sensitivity analysis of the potential effect of informative
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censoring of participants with HIV-1 seroconversion that
assumed increased risk for HSV-2 (1.5 times the placebo
rate) and no protective effect (because the study drug was
withheld at detection of HIV-1 seroconversion) produced
a narrow range of HRs over 1000 simulations (median,
0.697 [CI, 0.496 to 0.998]) (Table 2), indicating little
sensitivity to censoring.
Tenofovir Exposure and HSV-2 Protection
We compared plasma tenofovir levels among the 79
case participants with and 160 control participants without
HSV-2 seroconversion randomly selected from the active
PrEP groups. Overall, 76.8% of control participants had
detectable tenofovir (⬎0.3 ng/mL) compared with 75.9%
of case participants at the visit where HSV-2 infection was
first detected, and detection of tenofovir was not associated
with HSV-2 protection (adjusted HR, 1.72 [CI, 0.86 to
3.44]; P ⫽ 0.123).
DISCUSSION
In this secondary analysis within a randomized,
placebo-controlled trial of PrEP for HIV-1 prevention among
4747 HIV-1–serodiscordant couples, oral tenofovir-based
PrEP reduced HSV-2 acquisition by 30% compared with
placebo among initially HSV-2–seronegative persons. In
the subgroup analysis of participants with known exposure
to HSV-2 due to having a partner co-infected with HIV-1
and HSV-2, oral tenofovir-based PrEP reduced HSV-2
seroincidence by 33%. This is, to our knowledge, the first
evidence of efficacy of daily oral tenofovir-based PrEP in
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 Original Research HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis

Table 2. HSV-2 Seroincidence, by Study Group

Variable Combined Treatment Group Placebo

(Tenofovir or FTC–TDF)

Participants, n Events, n Person-Years Incidence, Participants, n Events, n Person-Years Incidence,

events per 100 events per 100
person-years person-years
Overall 1041 79 1422.2 5.55 481 52 672.0 7.74

Sex
Male 830 60 1143.9 5.25 389 42 556.9 7.54
Female 211 19 278.3 6.83 92 10 115.1 8.69

Circumcision among HIV-1/HSV-2–

seronegative men
Circumcised 491 35 649.0 5.39 239 28 337.8 8.29
Uncircumcised 339 25 494.9 5.05 150 14 219.1 6.39

Baseline plasma HIV-1 RNA level of

HIV-1–infected partner
⬍50 000 copies/mL 888 64 1226.2 5.22 392 41 548.9 7.47
ⱖ50 000 copies/mL 141 15 186.5 8.04 85 8 121.9 6.56

Baseline HSV-2 status of

HIV-1–infected partner
Positive 722 69 987.5 6.99 322 45 445.5 10.10
Negative 297 7 402.1 1.74 152 6 219.4 2.73

Baseline CD4 count of

HIV-1–infected partner
⬍0.350 ⫻ 109 cells/L 193 22 266.0 8.27 81 4 128.9 3.10
ⱖ0.350 ⫻ 109 cells/L 848 57 1156.2 4.93 400 48 543.1 8.84

FTC–TDF ⫽ emtricitabine in combination with tenofovir disoproxil fumarate; HR ⫽ hazard ratio; HSV-2 ⫽ herpes simplex virus type 2.
* The HR was 0.69 (95% CI, 0.49 – 0.99; P ⫽ 0.041) in the Cox proportional hazards model and 0.70 (CI, 0.49 –1.00; P ⫽ 0.053) in the marginal structural model when
each model was stratified by site. To account for potential informative censoring of participants with HIV-1 seroconversion (n ⫽ 18 censored at the time of seroconversion,
with no additional HSV-2 testing after that point), we conducted simulation modeling to assess the effect of following participants after seroconversion. We simulated a
conservative scenario 1000 times under the assumption that the risk for HSV-2 acquisition after HIV-1 seroconversion was elevated (1.5 times the HSV-2 seroconversion rate
in the placebo group among those who were HIV-1– uninfected) and the same in the preexposure prophylaxis and placebo groups (HR, 1). In this scenario, the overall
median HR was 0.697 (CI, 0.496 – 0.998)— essentially the same as the HRs from the proportional hazards and marginal structural models—suggesting that censoring
participants at the time of HIV-1 seroconversion had little effect on the overall findings.
† Values in bold are statistically significant.
‡ Test for effect modification.

providing protection against HSV-2 in a study population
with high adherence to daily oral PrEP.
The efficacy of tenofovir to reduce the risk for HSV-2
acquisition found in this study is consistent with the
HSV-2 protective effect of 51% observed with pericoital
use of topical 1% tenofovir gel (6, 8). Topical use of teno-
fovir or high adherence to daily dosing of oral tenofovir
may be needed to achieve sufficient levels to provide pro-
tection against HSV-2 given that the 90% effective con-
centration (EC90) of tenofovir for HSV-2 is high (10, 11).
We did not find a relationship between detection of teno-
fovir in plasma and protection against HSV-2, although
similar analyses for HIV-1 protection among the HIV-1–
uninfected participants in the Partners PrEP Study showed
an association (2). The lack of relationship between detec-
tion of tenofovir in plasma and protection against HSV-2
may indicate either less ability to discern a concentration–
response relationship between tenofovir exposure and
HSV-2 protection if the actual protective effect is modest
or less precise timing of drug exposure and HSV-2 sero-
conversion due to assessing HSV-2 serostatus up to every 6
16 1 July 2014 Annals of Internal Medicine Volume 161 • Number 1
months (in contrast to HIV-1 serostatus, which was as-
sessed monthly). In addition, 80% of the HSV-2–suscep-
tible participants in this study were men; the biology of
heterosexual HSV-2 transmission with respect to HSV-2
target cells and the bioavailability of oral tenofovir in pe-
nile epithelium are not well-characterized.
Protection from HSV-2 with daily oral tenofovir-
based PrEP is biologically plausible given recent in vitro
data showing that tenofovir inhibits HSV-2 replication in
epithelial raft cultures, a mouse model, and ex vivo human
lymphoid and cervicovaginal tissue from persons monoin-
fected with HSV-2 and those co-infected with HIV-1 and
HSV-2 (10). Steady-state tenofovir concentrations in the
genital tract after daily oral FTC–TDF are approximately
100 ng/mL (22), and in vitro studies indicate HSV sup-
pression at tenofovir concentrations between 10 and 200
␮g/mL (10), which would only be achieved in the context
of high adherence to daily oral dosing and accumulation of
active metabolites in the genital tract. The lack of HSV-2
protection with oral FTC–TDF among men who have sex
with men in another PrEP trial was potentially due to
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 HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis Original Research

lower adherence in that study (23); only about half of

Table 2—Continued
participants had objective evidence of PrEP adherence (1)
compared with more than 80% in our study (2). Given the
Proportional Hazards Model* Marginal Structural Model*
strong association between adherence and HIV-1 protec-
tion with daily oral dosing of PrEP, new formulations for
HR vs. Placebo P Value† HR vs. Placebo P Value†
(95% CI) (95% CI)
sustained delivery of PrEP products, such as an intravaginal
ring containing tenofovir, may provide a less user-
0.70 (0.49–0.99) 0.047 0.69 (0.49–0.99) 0.041 dependent formulation with sustained release of tenofovir
in the genital tract (24).
0.67‡
Our results and those of others indicate that tenofovir-
0.67 (0.45–1.00) 0.048 0.66 (0.45–0.99) 0.042
0.81 (0.38–1.74) 0.59 0.77 (0.36–1.67) 0.51 based PrEP may have prophylactic activity against other
viruses in addition to HIV-1. Tenofovir-containing ART
0.58‡
regimens have been shown to be associated with reduced
0.62 (0.38–1.02) 0.059 0.61 (0.37–1.00) 0.051 incidence of hepatitis B infection in HIV-1–infected per-
0.78 (0.41–1.50) 0.46 0.76 (0.40–1.47) 0.42 sons (25), which is consistent with in vitro and in vivo
0.24‡
activity of tenofovir (and emtricitabine) in persons with
chronic hepatitis B infection (26, 27). The efficacy of
0.68 (0.46–1.01) 0.057 0.67 (0.45–0.99) 0.049 tenofovir-containing ART regimens has not been evaluated
1.19 (0.51–2.82) 0.69 1.19 (0.52–2.73) 0.68
for HSV-2 protection in HIV-1–infected persons who are
0.50‡ HSV-2– uninfected. Ongoing studies are evaluating the
therapeutic efficacy of tenofovir in reducing HSV-2 shed-
0.67 (0.46–0.98) 0.038 0.65 (0.44–0.95) 0.024
0.62 (0.21–1.85) 0.39 0.63 (0.21–1.90) 0.41
ding in persons with chronic HSV-2 infection with and
without HIV-1 infection. One small study in persons co-
0.003‡ infected with HIV-1 and HSV-2 found that tenofovir-
2.50 (0.86–7.26) 0.092 2.24 (0.78–6.48) 0.140
containing ART was not associated with reduced rates of
0.55 (0.37–0.81) 0.002 0.55 (0.37–0.80) 0.002 HSV-2 shedding, but the study had limited power to de-
tect a difference (28).
Interventions to reduce the risk for HSV-2 acquisition
are a high priority. Incidence of HSV-2 is high in popula-

Figure 2. Cumulative probability of HSV-2 seroconversion in the active PrEP (tenofovir and FTC–TDF) versus placebo groups.

0.20
Cumulative Probability of HSV-2 Seroconversion

PrEP
0.15
Placebo

0.10

0.05

0.00

0 3 6 9 12 15 18 21 24 27 30

Months Since Start

At risk, n
PrEP 1025 973 948 774 576 386 130
Placebo 473 438 428 371 279 189 62

FTC–TDF ⫽ emtricitabine in combination with tenofovir disoproxil fumarate; HSV-2 ⫽ herpes simplex virus type 2; PrEP ⫽ preexposure prophylaxis.

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 Original Research HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis
tions worldwide; annualized incidence was 20% among
young South African women (6) and 15% among HIV-1–
serodiscordant couples in Kenya who reported a high rate
of condom use (29). In addition, observational data indi-
cate a 3-fold increased risk for HIV-1 acquisition due to
prevalent HSV-2 infection and up to a 6-fold increase with
incident HSV-2 infection (30). Interventions to reduce the
risk for HSV-2 transmission and acquisition are limited.
Condoms are estimated to reduce HSV-2 acquisition by
30% (31), which is substantially lower than the 80% effi-
cacy of condoms in reducing the per-contact risk for
HIV-1 acquisition (32), and medical circumcision pro-
vided modest protection against HSV-2 acquisition in
HIV-1– uninfected men in 2 of 3 trials (33–35). Candidate
preventive HSV-2 vaccines to date have not shown efficacy
in preventing HSV-2 infection (36, 37). Widely used
agents for treatment of HSV-2 infection have shown mixed
results when used for prevention of HSV-2 infection, with
1 study finding that valacyclovir, 500 mg once daily, re-
duced HSV-2 transmission by 50% to partners of HSV-2–
infected persons who were not infected with HIV-1 (38),
but other studies found that acyclovir, 400 mg twice daily,
did not reduce HSV-2 transmission to partners of persons
co-infected with HIV-1 and HSV-2 (39) or HSV-2 acqui-
sition in HIV-1– uninfected persons (40, 41). No studies
are available of valacyclovir or acyclovir for primary pro-
phylaxis against HSV-2 acquisition.
Strengths of this study include the use of a blinded
end point determination process based on the best avail-
able HSV-2 serologic testing algorithm and sufficient
power with 131 end points to determine modest effective-
ness. Subgroup analysis based on known exposure to an
HSV-2–infected partner was feasible because of the couples
design. The consistency of results between the proportional
hazards and marginal structural models indicates that
intention-to-treat assumptions were appropriate and that
significant confounding was not present in the subsample
of initially HSV-2–seronegative persons and was not in-
duced by censoring at HIV-1 seroconversion or loss to
follow-up.
Limitations of this study include the inability to detect
and exclude individuals with acute HSV-2 infection at
baseline due to a lack of laboratory methods. Ten percent
of incident HSV-2 infections occurred in partnerships
where the HIV-1–infected partner was HSV-2–
seronegative at baseline, but laboratory methods are not
available for linkage of HSV-2 strains. Because of availabil-
ity of testing and samples, we were unable to assess the
timing of HSV-2 acquisition with greater precision than
according to the schedule of follow-up testing we per-
formed, which may have limited our ability to demonstrate
an association between HSV-2 protection and plasma
tenofovir detection. Finally, we censored participants after
HIV-1 seroconversion because the study drug was discon-
tinued and we could not determine HSV-2 seroconversion
in these participants; however, sensitivity analyses indicated
18 1 July 2014 Annals of Internal Medicine Volume 161 • Number 1
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that the HRs for HSV-2 acquisition were relatively stable
despite this potentially informative censoring.
In summary, tenofovir-based PrEP provides modest
protection against HSV-2. Incidence was 7.7 per 100
person-years in the placebo group of this study, nearly
4-fold greater than the HIV-1 incidence (2.0 per 100
person-years). Given the high prevalence of HSV-2 in
HIV-1–infected persons, and given that HSV-2 is a signif-
icant risk factor for HIV-1 acquisition, identifying effective
primary prevention strategies for HSV-2 is a public health
priority. The HSV-2 protective effects of oral tenofovir-
based PrEP add benefit to the high protection against
HIV-1 in populations who are often at risk for HIV-1 and
HSV-2.
From University of Washington and Fred Hutchinson Cancer Research
Center, Seattle, Washington; Johns Hopkins University, Baltimore,
Maryland; Indiana University, Indianapolis, Indiana; and Makerere Uni-
versity, Kampala, Uganda.
Note: All authors vouch for the completeness and accuracy of the data
presented.
Acknowledgment: The authors thank the study participants and the
study team.
Grant Support: By the Bill & Melinda Gates Foundation (OOP47674).
Disclosures: Disclosures can be viewed at www.acponline.org/authors
/icmje/ConflictOfInterestForms.do?msNum⫽M13-2471.
Reproducible Research Statement: Study protocol and statistical code:
Available from Dr. Celum (e-mail, ccelum@uw.edu). Data set: Portions
of the analytic data set are available to approved individuals through
written agreement with Dr. Celum (e-mail, ccelum@uw.edu).
Requests for Single Reprints: Connie Celum, MD, MPH, University
of Washington, 325 Ninth Avenue, UW Box 359927, Seattle, WA
98104.
Current author addresses and author contributions are available at
www.annals.org.
References
1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al;
iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men
who have sex with men. N Engl J Med. 2010;363:2587-99. [PMID: 21091279]
2. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al;
Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in
heterosexual men and women. N Engl J Med. 2012;367:399-410. [PMID:
22784037]
3. Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leet-
hochawalit M, et al; Bangkok Tenofovir Study Group. Antiretroviral prophy-
laxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bang-
kok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3
trial. Lancet. 2013;381:2083-90. [PMID: 23769234]
4. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi
TM, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for het-
erosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-34.
[PMID: 22784038]
www.annals.org
 HSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis
5. Balzarini J, Holy A, Jindrich J, Naesens L, Snoeck R, Schols D,
et al. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R)
enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and
in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-
diaminopurine. Antimicrob Agents Chemother. 1993;37:332-8. [PMID:
8452366]
6. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C,
Mansoor LE, et al; CAPRISA 004 Trial Group. Effectiveness and safety of
tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in
women. Science. 2010;329:1168-74. [PMID: 20643915]
7. Tan D. Potential role of tenofovir vaginal gel for reduction of risk of herpes
simplex virus in females. Int J Womens Health. 2012;4:341-50. [PMID:
22927765]
8. Centre for the AIDS Programme of Research in South Africa. Effectiveness
& safety of vaginal microbicide 1% tenofovir gel for prevention of HIV infection
in women. Congella, South Africa: Centre for the AIDS Programme of Research
in South Africa; 2010. Accessed at www.conrad.org/media/news/92
_CAPRISA%20004%20Results.pdf on 7 May 2014.
9. Karim SS, Kashuba AD, Werner L, Karim QA. Drug concentrations after
topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV
prevention in women. Lancet. 2011;378:279-81. [PMID: 21763939]
10. Andrei G, Lisco A, Vanpouille C, Introini A, Balestra E, van den Oord J,
et al. Topical tenofovir, a microbicide effective against HIV, inhibits herpes sim-
plex virus-2 replication. Cell Host Microbe. 2011;10:379-89. [PMID:
22018238]
11. Schwartz JL, Rountree W, Kashuba AD, Brache V, Creinin MD, Poin-
dexter A, et al. A multi-compartment, single and multiple dose pharmacokinetic
study of the vaginal candidate microbicide 1% tenofovir gel. PLoS One. 2011;6:
e25974. [PMID: 22039430]
12. Mujugira A, Baeten JM, Donnell D, Ndase P, Mugo NR, Barnes L, et al;
Partners PrEP Study Team. Characteristics of HIV-1 serodiscordant couples
enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1
prevention. PLoS One. 2011;6:e25828. [PMID: 21998703]
13. Lingappa J, Nakku-Joloba E, Magaret A, Friedrich D, Dragavon J, Kam-
bugu F, et al. Sensitivity and specificity of herpes simplex virus-2 serological
assays among HIV-infected and uninfected urban Ugandans. Int J STD AIDS.
2010;21:611-6. [PMID: 21097732]
14. Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western
blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for
detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin
Microbiol. 1988;26:662-7. [PMID: 2835389]
15. Keller MJ, Madan RP, Torres NM, Fazzari MJ, Cho S, Kalyoussef S, et al.
A randomized trial to assess anti-HIV activity in female genital tract secretions
and soluble mucosal immunity following application of 1% tenofovir gel. PLoS
One. 2011;6:e16475. [PMID: 21283552]
16. Dropulic LK, Cohen JI. Update on new antivirals under development for the
treatment of double-stranded DNA virus infections. Clin Pharmacol Ther. 2010;
88:610-9. [PMID: 20881959]
17. Prentice RL, Gloeckler LA. Regression analysis of grouped survival data with
application to breast cancer data. Biometrics. 1978;34:57-67. [PMID: 630037]
18. Hernán MA, Brumback B, Robins JM. Marginal structural models to esti-
mate the causal effect of zidovudine on the survival of HIV-positive men. Epide-
miology. 2000;11:561-70. [PMID: 10955409]
19. Breslow NE, Lumley T, Ballantyne CM, Chambless LE, Kulich M. Im-
proved Horvitz-Thompson estimation of model parameters from two-phase strat-
ified samples: applications in epidemiology. Stat Biosci. 2009;1:32. [PMID:
20174455]
20. Haberer JE, Baeten JM, Campbell J, Wangisi J, Katabira E, Ronald A, et al.
Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort
within a clinical trial of serodiscordant couples in East Africa. PLoS Med. 2013;
10:e1001511. [PMID: 24058300]
21. Lumley T. Complex Surveys: A Guide to Analysis Using R. Hoboken, NJ:
J Wiley; 2010.
22. Dumond JB, Yeh RF, Patterson KB, Corbett AH, Jung BH, Rezk NL,
et al. Antiretroviral drug exposure in the female genital tract: implications for oral
pre- and post-exposure prophylaxis. AIDS. 2007;21:1899-907. [PMID:
17721097]
www.annals.org
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930448/ by a Suny Health Sciences Ctr User on 06/17/2017
Original Research
23. Lama J, Mayer K, Schechter M, Kallas E, Bekker LG, Chariyalertsak S,
et al. Oral TDF and its impact in HSV-2 acquisition and clinical expression
[Abstract]. Presented at the 18th Conference on Retroviruses and Opportunistic
Infections, Boston, Massachusetts, 27 February–2 March 2011. Abstract no.
1002.
24. Mesquita PM, Rastogi R, Segarra TJ, Teller RS, Torres NM, Huber AM,
et al. Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of
HIV and herpes simplex virus infection. J Antimicrob Chemother. 2012;67:
1730-8. [PMID: 22467632]
25. Gatanaga H, Hayashida T, Tanuma J, Oka S. Prophylactic effect of anti-
retroviral therapy on hepatitis B virus infection. Clin Infect Dis. 2013;56:1812-9.
[PMID: 23487374]
26. Price H, Dunn D, Pillay D, Bani-Sadr F, de Vries-Sluijs T, Jain MK, et al.
Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic
review and meta-analysis. PLoS One. 2013;8:e68152. [PMID: 23874527]
27. Soriano V, Poveda E, Vispo E, Barreiro P. Hepatitis B in HIV-infected
patients. Clin Liver Dis. 2013;17:489-501. [PMID: 23905818]
28. Tan DH, Kaul R, Raboud JM, Walmsley SL. No impact of oral tenofovir
disoproxil fumarate on herpes simplex virus shedding in HIV-infected adults.
AIDS. 2011;25:207-10. [PMID: 21150556]
29. Muiru AN, Guthrie BL, Bosire R, Merkel M, Liu AY, Choi RY, et al.
Incident HSV-2 infections are common among HIV-1-discordant couples. J In-
fect Dis. 2013;208:1093-101. [PMID: 23840044]
30. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ.
Herpes simplex virus 2 infection increases HIV acquisition in men and women:
systematic review and meta-analysis of longitudinal studies. AIDS. 2006;20:73-
83. [PMID: 16327322]
31. Martin ET, Krantz E, Gottlieb SL, Magaret AS, Langenberg A, Stanberry
L, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acqui-
sition. Arch Intern Med. 2009;169:1233-40. [PMID: 19597073]
32. Hughes JP, Baeten JM, Lingappa JR, Magaret AS, Wald A, de Bruyn G,
et al; Partners in Prevention HSV/HIV Transmission Study Team. Determi-
nants of per-coital-act HIV-1 infectivity among African HIV-1-serodiscordant
couples. J Infect Dis. 2012;205:358-65. [PMID: 22241800]
33. Mahiane SG, Legeai C, Taljaard D, Latouche A, Puren A, Peillon A, et al.
Transmission probabilities of HIV and herpes simplex virus type 2, effect of male
circumcision and interaction: a longitudinal study in a township of South Africa.
AIDS. 2009;23:377-383. [PMID: 19198042]
34. Tobian AA, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, Laeyendecker
O, et al. Male circumcision for the prevention of HSV-2 and HPV infections and
syphilis. N Engl J Med. 2009;360:1298-309. [PMID: 19321868]
35. Mehta SD, Moses S, Parker CB, Agot K, Maclean I, Bailey RC. Circum-
cision status and incident herpes simplex virus type 2 infection, genital ulcer
disease, and HIV infection. AIDS. 2012;26:1141-9. [PMID: 22382150]
36. Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, et al;
Herpevac Trial for Women. Efficacy results of a trial of a herpes simplex vaccine.
N Engl J Med. 2012;366:34-43. [PMID: 22216840]
37. Johnston C, Koelle DM, Wald A. Current status and prospects for develop-
ment of an HSV vaccine. Vaccine. 2014;32:1553-60. [PMID: 24016811]
38. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al; Valacy-
clovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the
risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20. [PMID:
14702423]
39. Mujugira A, Magaret AS, Celum C, Baeten JM, Lingappa JR, Morrow RA,
et al; Partners in Prevention HSV/HIV Transmission Study Team. Daily acy-
clovir to decrease herpes simplex virus type 2 (HSV-2) transmission from HSV-
2/HIV-1 coinfected persons: a randomized controlled trial. J Infect Dis. 2013;
208:1366-74. [PMID: 23901094]
40. Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, et al;
HPTN 039 Protocol Team. Effect of aciclovir on HIV-1 acquisition in herpes
simplex virus 2 seropositive women and men who have sex with men: a ran-
domised, double-blind, placebo-controlled trial. Lancet. 2008;371:2109-19.
[PMID: 18572080]
41. Watson-Jones D, Weiss HA, Rusizoka M, Changalucha J, Baisley K, Mug-
eye K, et al; HSV trial team. Effect of herpes simplex suppression on incidence of
HIV among women in Tanzania. N Engl J Med. 2008;358:1560-71. [PMID:
18337596]
1 July 2014 Annals of Internal Medicine Volume 161 • Number 1 19
 Current Author Addresses: Drs. Celum, Donnell, Hong, and Baeten;
Ms. Thomas; and Mr. Mujugira: University of Washington, 325 Ninth
Avenue, UW Box 359927, Seattle, WA 98104.
Dr. Morrow: Fred Hutchinson Cancer Research Center, 1100 Fairview
Avenue North, LE-500, Seattle, WA 98109.
Dr. Hendrix: Department of Medicine, Johns Hopkins University, 600
North Wolfe Street, Harvey 502, Baltimore, MD 21287-5554.
Dr. Fife: Department of Medicine, Indiana University, Emerson
H/Room 435, 545 Barnhill Drive, Indianapolis, IN 46202.
Dr. Nakku-Joloba: School of Public Health, Makerere University, PO
Box 22418, Plot 106, Block 213, Bukoto, Kampala, Uganda.
Author Contributions: Conception and design: C. Celum, D. Donnell,
J.M. Baeten.
Analysis and interpretation of the data: C. Celum, R.A. Morrow,
D. Donnell, T. Hong, C.W. Hendrix, K.K. Thomas, K.H. Fife, J.M.
Baeten.
Drafting of the article: C. Celum, D. Donnell, J.M. Baeten.
Critical revision of the article for important intellectual content: C.
Celum, D. Donnell, K.H. Fife, E. Nakku-Joloba, J.M. Baeten.
Final approval of the article: C. Celum, R.A. Morrow, D. Donnell, C.W.
Hendrix, K.H. Fife, E. Nakku-Joloba, A. Mujugira, J.M. Baeten.
Provision of study materials or patients: K.H. Fife, A. Mujugira, J.M.
Baeten.
Statistical expertise: D. Donnell, T. Hong, K.K. Thomas.
Obtaining of funding: C. Celum, J.M. Baeten.
Administrative, technical, or logistic support: E. Nakku-Joloba, A.
Mujugira, J.M. Baeten.
Collection and assembly of data: C. Celum, R.A. Morrow, D. Donnell,
C.W. Hendrix, K.H. Fife, E. Nakku-Joloba, A. Mujugira, J.M. Baeten.
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APPENDIX: PARTNERS PREP STUDY TEAM
University of Washington Coordinating Center and
Central Laboratories, Seattle, Washington
Connie Celum (principal investigator and protocol co-
chair), Jared M. Baeten (medical director and protocol co-chair),
Deborah Donnell (protocol statistician), Robert W. Coombs
(University of Washington Retrovirology Laboratory), Anne
Cent (University of Washington Virology Laboratory), and Jai-
ram Lingappa (University of Washington International Clinical
Research Center Biorepository).
Study Sites and Principal Investigators
Eldoret, Kenya (Moi University and Indiana University):
Kenneth Fife and Edwin Were; Kabwohe, Uganda (Kabwohe
Clinical Research Center): Elioda Tumwesigye; Jinja, Uganda
(Makerere University and University of Washington): Patrick
Ndase and Elly Katabira; Kampala, Uganda (Makerere Univer-
sity): Elly Katabira and Allan Ronald; Kisumu, Kenya (Kenya
Medical Research Institute and University of California, San
Francisco): Elizabeth Bukusi and Craig Cohen; Mbale, Uganda
(The AIDS Support Organization and Centers for Disease
Control and Prevention–Uganda): Jonathan Wangisi, James
Campbell, and Jordan Tappero; Nairobi, Kenya (University of
Nairobi and University of Washington): James Kiarie, Carey Far-
quhar, and Grace John-Stewart; Thika, Kenya (University of
Nairobi and University of Washington): Nelly Rwamba Mugo;
Tororo, Uganda (Centers for Disease Control and Prevention–
Uganda and The AIDS Support Organization): James Campbell,
Jordan Tappero, and Jonathan Wangisi.
Data management was provided by DF/Net Research (Seat-
tle, Washington), and site laboratory oversight was provided by
Contract Laboratory Services (University of the Witwatersrand,
Johannesburg, South Africa).
1 July 2014 Annals of Internal Medicine Volume 161 • Number 1
 CORRECTION: TENOFOVIR AND EMTRICITABINE–TENOFOVIR
PREEXPOSURE PROPHYLAXIS FOR HERPES SIMPLEX VIRUS
TYPE 2
An article (1) was missing the Intervention section of its ab-
stract. The section should read as follows:
Once-daily oral tenofovir disoproxil fumarate (TDF), alone or
combined with emtricitabine (FTC-TDF), compared with placebo.
This has been corrected in the online version.

Reference
1. Celum C, Morrow RA, Donnell D, Hong T, Hendrix CW, Thomas KK, et al.
Daily oral tenofovir and emtricitabine–tenofovir preexposure prophylaxis reduces her-
pes simplex virus type 2 acquisition among heterosexual HIV-1–uninfected men and
women: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;161:11-9.
[PMID: 24979446] doi: 10.7326/M13-2471

1 July 2014 Annals of Internal Medicine Volume 161 • Number 1 www.annals.org

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