The Journal of Infectious Diseases
MAJOR ARTICLE
Periodic Presumptive Treatment for Vaginal Infections
May Reduce the Incidence of Sexually Transmitted
Bacterial Infections
Jennifer E. Balkus,1,2 Lisa E. Manhart,2,3 Jeannette Lee,5 Omu Anzala,7 Joshua Kimani,8 Jane Schwebke,6 Juma Shafi,8 Charles Rivers,6 Emanuel Kabare,8 and
R. Scott McClelland2,4,8
1
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 2Department of Global Health, 3Department of Epidemiology, and 4Department of Medicine, University of
Washington, Seattle; 5Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock; 6Department of Medicine, University of Alabama at Birmingham; 7Department of Medical
Microbiology, and 8University of Nairobi Institute for Tropical and Infectious Diseases, University of Nairobi, Kenya
Background. Bacterial vaginosis (BV) may increase women’s susceptibility to sexually transmitted infections (STIs). In a randomized trial of periodic presumptive treatment (PPT) to reduce vaginal infections, we observed a significant reduction in BV. We
further assessed the intervention effect on incident Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium infection.
Methods. Nonpregnant, human immunodeficiency virus–uninfected women from the United States and Kenya received intravaginal metronidazole (750 mg) plus miconazole (200 mg) or placebo for 5 consecutive nights each month for 12 months. Genital
fluid specimens were collected every other month. Poisson regression models were used to assess the intervention effect on STI
acquisition.
Results. Of 234 women enrolled, 221 had specimens available for analysis. Incidence of any bacterial STI (C. trachomatis,
N. gonorrhoeae, or M. genitalium infection) was lower in the intervention arm, compared with the placebo arm (incidence rate
ratio [IRR], 0.54; 95% confidence interval [CI], .32–.91). When assessed individually, reductions in STI incidences were similar
but not statistically significant (IRRs, 0.50 [95% confidence interval {CI}, .20–1.23] for C. trachomatis infection, 0.56 [95% CI,
.19–1.67] for N. gonorrhoeae infection, and 0.66 [95% CI, .38–1.15] for M. genitalium infection).
Conclusions. In addition to reducing BV, this PPT intervention may also reduce the risk of bacterial STI among women. Because
BV is highly prevalent, often persists, and frequently recurs after treatment, interventions that reduce BV over extended periods could
play a role in decreasing STI incidence globally.
Keywords. bacterial vaginosis; Chlamydia trachomatis; Neisseria gonorrhoeae; Mycoplasma genitalium; vaginal health interventions; periodic presumptive treatment.
With >500 million new cases of sexually transmitted infections
(STIs) each year [1, 2], the development of innovative strategies
for STI prevention is a global public health priority. Chlamydia trachomatis infection and Neisseria gonorrhoeae infection
are the most prevalent bacterial STIs, and there is emerging
evidence in support of Mycoplasma genitalium as a sexually
transmitted pathogen in women [1, 3]. C. trachomatis, N. gonorrhoeae, and M. genitalium often go undetected because many
infections are asymptomatic [4, 5]. These infections are common among reproductive-aged women and are associated
with serious adverse reproductive health outcomes, including
Received 18 November 2015; accepted 23 January 2016; published online 4 February 2016.
Presented in part: Infectious Disease Society of Obstetrics and Gynecology, Stowe, Vermont,
7–9 August 2014; World HIV and STI Congress, Brisbane, Australia, 13–16 September 2015.
Correspondence: J. E. Balkus, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N,
M2-C200, PO Box 19024, Seattle, WA 98109-1024 ([email protected]).
The Journal of Infectious Diseases® 2016;213:1932–7
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail [email protected].
DOI: 10.1093/infdis/jiw043
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cervicitis, pelvic inflammatory disease (PID), infertility, ectopic
pregnancy, neonatal infections, and human immunodeficiency
virus (HIV) acquisition [3, 6–8].
The vaginal microenvironment plays an important role in
mediating STI susceptibility [9]. Several prospective studies
have reported an association between abnormal vaginal microbiota, in particular bacterial vaginosis (BV) and depletion of
Lactobacillus species, and increased risk of STI acquisition
[10–15]. In contrast, a healthy vaginal microbiota consisting
primarily of Lactobacillus species has been associated with a
lower risk of STI acquisition [13, 14, 16]. Furthermore, in an
open-label trial involving 107 US women with asymptomatic
BV determined on the basis of the Nugent score, those who received intravaginal metronidazole gel for 5 days, followed by
twice weekly use for 6 months, had a lower incidence of STI
(defined as a combined outcome of C. trachomatis infection,
N. gonorrhoeae infection, T. vaginalis infection, herpes simplex
virus [HSV] infection, or PID) while receiving treatment, compared with those who received standard of care treatment [10].
The results from this study provide preliminary evidence in
support of the hypothesis that improving vaginal health
through treatment of asymptomatic BV could reduce STI incidence. However, further investigation to confirm these findings
is warranted, including additional research among women from
resource-limited settings.
We recently completed a randomized, double-blinded, placebo-controlled trial of monthly periodic presumptive treatment
for 12 months to reduce bacterial vaginosis and vulvovaginal candidiasis among US and Kenyan women [17]. Over 1 year, the intervention significantly reduced the proportion of visits in which
BV was detected, compared with placebo; the proportion of visits
in which vulvovaginal candidiasis was detected were similar by
study arm. Using data from this multisite randomized trial, we
assessed the effect of the intervention on the acquisition of C. trachomatis, N. gonorrhoeae, and M. genitalium.
monthly follow-up visits, data were collected on sexual behaviors, intravaginal practices, contraceptive use, study product use,
and genital tract symptoms. Participants underwent adherence
counseling, and a urine pregnancy test was performed. Nonpregnant participants received a 1-month supply of study product
and free male condoms. Participants with symptomatic vulvovaginitis, vaginal discharge, or vaginal itching received treatment with
open-label oral metronidazole (400 mg or 500 mg) twice daily for
7 days plus single-dose oral fluconazole (150 mg), in addition to
study product. In addition, during follow-up visits at months 2, 4,
6, 8, 10, and 12, participants underwent a physical examination,
including a pelvic speculum examination with collection of genital
swab specimens for diagnosis of genital tract infections. If a participant missed an examination visit, a physical examination was
performed at her next follow-up visit.
METHODS
Laboratory Procedures
Study Population and Procedures
This is a secondary analysis of data from women participating
in the Preventing Vaginal Infections (PVI) trial, a doubleblinded, randomized, controlled trial that assessed the effect
of monthly periodic presumptive treatment (PPT) by using
topical metronidazole (750 mg) with miconazole (200 mg) intravaginal suppositories versus matching placebo nightly for 5
consecutive nights each month for 12 months to reduce
rates of BV and vulvovaginal candidiasis (clinical trials registration NCT01230814). Detailed methods and results for the trial
have been described previously [17]. Briefly, 234 high-risk
women from 3 sites in Kenya and 1 site in the United States
were enrolled between May 2011 and August 2012. Eligible
women were 18–45 years of age, HIV-1 uninfected, not pregnant or breastfeeding, and sexually active (defined as a selfreported frequency of at least 4 episodes of vaginal sex in the
past month) and had BV by Nugent’s score [18] and/or VVC
by saline/potassium hydroxide wet preparation plus positive
results of culture for yeast on Sabouraud agar, and/or Trichomonas vaginalis infection detected by a saline wet preparation at
screening. Eligible participants were randomly assigned in
equal proportions to receive either the intervention or matching
placebo. All participants provided written informed consent at
screening and enrollment. Participants were asked to provide
separate consent for the storage and future testing of biological
specimens, including those used for the present analysis. The
trial was approved by the human subjects research committees
at Kenyatta National Hospital (Nairobi, Kenya), the University
of Washington (Seattle), and the University of Alabama at
Birmingham.
At enrollment, structured face-to-face interviews were conducted to collect data on demographic, clinical, and behavioral
characteristics. Participants also received C. trachomatis and N.
gonorrhoeae testing at enrollment, and those with a diagnosis of
either infection were treated according to local guidelines. At
Genital fluid was collected using the Hologic/Gen-Probe Aptima Combo 2 system (Hologic/GenProbe; San Diego, California) at enrollment and follow-up months 2, 4, 6, 8, 10, and
12. Specimens collected at enrollment were tested for the presence of C. trachomatis and N. gonorrhoeae in accordance with
the manufacturer’s recommendations. The remainder of the enrollment specimen and all follow-up specimens were stored at
−80°C for future testing. At the completion of the study, stored
follow-up specimens were tested for C. trachomatis and N. gonorrhoeae per the manufacturer’s recommendations; for T. vaginalis, using the Hologic/Gen-Probe ASR assay; and for
M. genitalium, using a research-use only transcription TMA
assay with reagents provided by Hologic/Gen-Probe as part of
their ongoing research program. M. genitalium assay results
with a value of >40 000 relative light units were considered positive [19]. Vaginal Gram-stained slides were evaluated for BV by
using the Nugent score [18]. Saline and potassium hydroxide
wet preparations were examined for the presence of motile
trichomonads, clue cells, and yeast. Yeast culture was performed
on Sabouraud agar with a germ tube test to identify presumptive Candida albicans. At enrollment, blood specimens were
collected through venipuncture for HSV-2 testing, using the
HerpeSelect assay (Focus Technologies). An OD of >2.1 was
considered positive for participants in Kenya [20]. Enrollment
specimens from US participants were tested using kits that produced a dichotomous result (positive vs negative).
Statistical Analysis
Our primary objective was to assess the effect of the PVI trial
intervention on incident bacterial STIs during follow-up (combined outcome of incident C. trachomatis, N. gonorrhoeae, or
M. genitalium infection) in the subset of PVI trial participants
who consented to future testing of stored specimens. We also
conducted a secondary analysis to assess the effect of the intervention on C. trachomatis, N. gonorrhoeae, and M. genitalium
infection, each as a separate outcome. For each analysis, the
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Table 1. Baseline Characteristics of Participants in the Preventing
Vaginal Infections Trial Who Were Eligible for Secondary Analysis
Placebo Group
(n = 110)
Characteristic
Intervention
Group (n = 111)
Table 1 continued.
Characteristic
Placebo Group
(n = 110)
Intervention
Group (n = 111)
Condom use during sex in past week
Demographic characteristic
Age, y
Always
53 (48)
42 (38)
Intermittentlyb
11 (10)
12 (11)
Overall
29 (23–34)
30 (24–34)
Never
26 (24)
36 (32)
<25
29 (26)
33 (30)
No sex reported
20 (18)
21 (19)
Education duration, y
11 (8–12)
10 (8–13)
Sex partners in past week, no.
Partnership status
Married or living with a partner
29 (26)
34 (31)
Separated, divorced, or widowed
48 (44)
39 (35)
Never married
33 (30)
38 (34)
1 (1–2)
1 (1–2)
New sex partner in past week
23 (21)
22 (20)
Ever had anal sex
13 (12)
12 (11)
Clinical characteristic
Study site
C. trachomatis infection
8 (7)
8 (7)
N. gonorrhoeae infection
0 (0)
3 (3)
Birmingham, AL
26 (24)
27 (24)
M. genitalium infectionc
Kangemi area, Nairobi, Kenya
27 (25)
28 (25)
HSV-2 seropositived
Korogocho area, Nairobi, Kenya
28 (25)
28 (25)
T. vaginalis infectionc
6 (5)
10 (9)
Mombasa, Kenya
29 (26)
28 (25)
Vulvovaginal candidiasis
24 (22)
28 (25)
Bacterial vaginosise
40 (36)
41 (37)
Intermediate microbiotae
20 (18)
24 (22)
Normal microbiotae
50 (45)
46 (41)
Cervicitisf
14 (13)
18 (16)
Health history
Live births, no.
2 (1–3)
2 (1–3)
Current family planning method
None
16 (15)
23 (21)
Condoms only
30 (27)
31 (28)
Oral contraceptives
12 (11)
11 (10)
Injectable contraceptives
25 (23)
24 (22)
IUD
9 (8)
16 (14)
68 (62)
71 (64)
Data are no. (%) of women or median (interquartile range).
Abbreviations: C. trachomatis, Chlamydia trachomatis; HSV-2, herpes simplex virus type 2;
IUD, intrauterine device; M. genitalium, Mycoplasma genitalium; N. gonorrhoeae, Neisseria
gonorrhoeae.
10 (9)
4 (4)
Implant
9 (8)
5 (5)
Tubal ligation
5 (5)
10 (9)
Othera
3 (3)
3 (3)
Currently smoke cigarettes
10 (9)
20 (18)
c
One intervention participant was missing results at enrollment.
Vaginal washing in the past month
55 (50)
56 (50)
d
Kenyan participants with an OD of >2.1 were considered seropositive.
Ever engaged in sex in exchange for
goods/money/services
Vaginal sex acts in the past week, no.
60 (55)
2 (1–4)
59 (53)
2 (1–3)
population under study was restricted to participants who were
negative for all STIs (in the combined end point analysis) or for
the STI of interest (in analyses of individual STIs) at enrollment.
We calculated the incidence of the combined STI outcome and
each individual STI, with follow-up time censored following the
first incident infection. Since the sample size and number of STI
outcomes were small, we constructed Poisson regression models
to assess the effect of the intervention on the combined and individual bacterial STI outcomes. Differences in duration of participant follow-up were assessed using the Wilcoxon rank sum
test. All statistical tests were assessed using a 2-sided significance level of 0.05. Analyses were conducted using Stata, version 14.0 (StataCorp, College Station, Texas).
RESULTS
Of the 234 participants enrolled, 221 (94%) returned for followup visits and provided consent for future testing of stored specimens; 111 (50%) were in the intervention arm, and 110 (50%)
were in the placebo arm. Participant follow-up did not differ by
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Included the fertility awareness method (n = 2), vasectomy by partner (n = 1), Essure use
(n = 1), withdrawal (n = 1), and herbal pills (n = 1).
b
Defined as <100% but >0% of occasions. No condom use was reported among women
who reported sex in the past week.
e
Sexual behavior
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Assessed by the Nugent score, with 7–10 indicating bacterial vaginosis, 4–6 indicating
intermediate microbiota, and 0–3 indicating normal microbiota.
f
Defined as ≥30 polymorphonuclear leukocytes per high-powered field. One participant was
missing a baseline result.
study arm, with median of 11.2 months (interquartile range
[IQR], 11.1–11.6 months) in the intervention arm, compared
with 11.4 months (IQR, 11.2–11.7 months) in the placebo
arm (P = .12). Demographic, behavioral, and clinical characteristics at enrollment are presented by study arm in Table 1. Characteristics of participants in the intervention arm were generally
similar to those in the placebo arm.
The prevalences of C. trachomatis, N. gonorrhoeae, and M.
genitalium infections by study arm at enrollment are presented
in Table 1. Of these 3 STIs, M. genitalium was the most commonly detected at baseline, with an overall prevalence of 11.3%,
followed by C. trachomatis (7.2%), and N. gonorrhoeae (1.3%).
Incidences and effect estimates for each STI outcome are presented in Table 2. Consistent with the baseline STI prevalence,
the overall incidence of individual bacterial STIs was highest for
M. genitalium, with 52 incident cases detected during 155.0 person-years of follow-up (33.6 cases per 100 person-years), followed by C. trachomatis (11.7 cases per 100 person-years)
and N. gonorrhoeae (7.2 cases per 100 person-years). The
Table 2.
Effect of the Intervention on Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium Acquisition
STI Outcome, Study Group
Women, No.
Events, No.
Person-Years, No.
Incidencea (95% CI)
IRRb (95% CI)
P Value
.02
Combined STIs
Overallc
177
63
135.6
46.5 (36.3–59.5)
Intervention
84
22
67.4
32.6 (21.5–49.6)
0.54 (.32–.91)
Placebo
93
41
68.2
60.1 (44.3–81.7)
1.00
11.7 (7.6–17.9)
Individual STIs
C. trachomatis infection
Overall
205
21
179.6
Intervention
103
7
90.0
7.8 (3.7–16.3)
Placebo
102
14
89.6
15.6 (9.3–26.4)
Overall
218
14
193.3
7.2 (4.3–12.2)
Intervention
108
5
96.3
5.2 (2.2–12.5)
0.56 (.19–1.67)
Placebo
110
9
96.9
9.3 (4.8–17.8)
1.00
195
52
155.0
33.6 (25.6–44.0)
94
20
75.5
26.5 (17.1–41.1)
0.66 (.38–1.15)
101
32
79.5
40.3 (28.5–56.9)
1.00
0.50 (.20–1.23)
.13
1.00
N. gonorrhoeae infection
.30
M. genitalium infectiond
Overall
Intervention
Placebo
.14
Data are for the first incident STI, with follow-up censored at the time of first infection. Each model excludes participants with the STI(s) of interest present at baseline.
Abbreviations: CI, confidence interval; STI, sexually transmitted infection.
a
Data denote the number of new STIs per 100 person-years and only include the first STI detected.
b
Incidence rate ratios (IRRs) were calculated by Poisson regression models.
c
Defined as C. trachomatis or N. gonorrhoeae or M. genitalium infection.
d
In addition to the 25 participants with baseline M. genitalium infection, 1 participant was missing baseline results and excluded from the analysis, leaving 195 participants for analysis.
overall incidence of C. trachomatis, N. gonorrhoeae, or M. genitalium infection was 46.5 cases per 100 person-years.
Among participants who were negative for C. trachomatis,
N. gonorrhoeae, or M. genitalium at baseline, we observed a
significant reduction in the combined outcome of any incident
bacterial STI for participants in the intervention arm, compared with those in the placebo arm (incidence rate ratio,
0.54; 95% confidence interval, .32–.91; Table 2). The magnitude of the intervention effect was similar when each bacterial
STI outcome was assessed separately, although the individual
STI reductions were not statistically significant (Figure 1 and
Table 2).
STI susceptibility and interventions that improve vaginal health
by shifting the microbiota away from bacterial vaginosis and that
could lead to reductions in highly prevalent bacterial STIs.
With an estimated 211 million new infections globally each
year, C. trachomatis infection and N. gonorrhoeae infection are
the most prevalent bacterial STIs [1]. These infections are associated with adverse reproductive health outcomes, including PID,
DISCUSSION
Monthly periodic presumptive treatment with vaginal suppositories
coformulated with metronidazole and miconazole, an intervention that significantly reduced BV over 12 months of followup [17], may also reduce the risk of bacterial STIs among
women. We observed nearly a 50% reduction in the combined
outcome of C. trachomatis, N. gonorrhoeae, or M. genitalium infection among women in the intervention arm, compared with
those in the placebo arm. Similar magnitudes of reduction
were observed in incident C. trachomatis, N. gonorrhoeae, and
M. genitalium infections when assessed as separate outcomes, although the small sample size in this secondary analysis precluded
detection of significant associations. These data support the hypothesis that the vaginal microenvironment influences bacterial
Figure 1. Forest plot of incident rate ratios and 95% confidence intervals for outcomes of individual and combined sexually transmitted infections due to Chlamydia
trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium.
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chronic pelvic pain, ectopic pregnancy, infertility, and HIV acquisition [3, 4, 6, 7, 21, 22]. The majority of infections in women are
asymptomatic, and targeted screening approaches have been used
to identify those with infection [23, 24]. However, uptake of
screening remains low worldwide [25, 26], and cost and limited
diagnostic capacity make this approach impractical in resourcelimited settings. While efforts to improve bacterial STI screening
and diagnostic assays are ongoing, the high STI incidence in many
settings emphasizes the need for novel, effective prevention strategies. Such strategies may be even more effective in decreasing
STI-associated sequelae as compared to detection and treatment.
There is a growing body of evidence in support of
M. genitalium as a sexually transmitted pathogen that may be
causally associated with adverse outcomes in women [3]. The
prevalence of M. genitalium infection in our study was high,
and as illustrated here and by others, it can be detected at a frequency equal to or greater than that of other bacterial STIs [27].
Highly sensitive diagnostic tests for M. genitalium have only recently become commercially available and are not yet widely
used in clinical settings, limiting the opportunity for pathogen-specific detection and treatment, as well as for global
surveillance. Data are limited and conflicting regarding
the relationship between BV and M. genitalium. Several studies
have reported an increased risk of M. genitalium infection
among women with BV [15, 28], while others have observed
no association [29–31]. Finding from the present study demonstrate a decrease in M. genitalium infection among women in the
intervention arm, where there was also a significant reduction in
BV [17]. An alternative hypothesis for our observation could be
that the incidence of M. genitalium infection was reduced as a
result of treatment with metronidazole. However, metronidazole
has no known effect on M. genitalium [32]. In the absence of a
direct effect of metronidazole on M. genitalium, our findings lend
support to the hypothesis that reductions in BV due to the intervention may decrease susceptibility to M. genitalium infection.
The vaginal microbiome has been well characterized though
cultivation-based and molecular methods. Robust data from epidemiological studies indicate that the vaginal microbiota influences STI susceptibility [10–14]. However, mechanistic data
illustrating how the presence of BV or BV-associated bacteria
modifies STI susceptibility are limited. Immunologic, enzymatic, and metabolic mechanisms could operate independently or
in combination to enhance STI acquisition. Several lines of evidence provide a strong foundation for a biologic relationship
between BV and increased STI susceptibility. An acidic vaginal
pH and the presence of Lactobacillus species have been associated with decreased in vitro activity of C. trachomatis and
N. gonorrhoeae [33, 34]. Cervical mucus has the ability to trap
pathogens. However, this mucus barrier may be compromised
by mucin-degrading enzymes such as sialidase and mucinase,
which are produced by BV-associated bacteria. Loss of the protective mucus provides pathogens with unhindered access to
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target cells, increasing epithelial binding potential. Sialidase
also cleaves terminal sialic acids from glycoproteins, exposing
other sugars on their carbohydrate side chains, which can be
used as an energy source for bacteria. Other mechanisms,
such as use of indole, which is produced by several BVassociated species, by C. trachomatis could enable the bacteria
to overcome the bactericidal effects of interferon γ [36]. Biologic
mechanisms potentially driving the association between BV and
STI acquisition require further investigation.
Our analysis included a number of strengths, including data
collected as part of a multisite, multicountry clinical trial with
high adherence and retention. The intervention was evaluated
among women with a recent vaginal infection, since they
would be most likely to benefit from a vaginal health intervention, and STI outcomes were assessed at regular intervals by
using highly sensitive assays. Nonetheless, our findings should
be interpreted in the context of several limitations. Study participants were predominantly African or African American and
were recruited from populations at high-risk for STIs, including
HIV infection. The prevalence of BV is frequently higher
among African and African American women, compared
with other races [36]. It is unclear if the magnitude of the intervention effect would be the same in other populations where the
burden of BV may be lower. The PVI trial was powered to assess
the effect of the PPT intervention on BV and vulvovaginal
candidiasis. As a result, statistical power was insufficient to
adequately assess individual STI outcomes. However, we did observe a significant effect of the intervention on any bacterial STI
(C. trachomatis, N. gonorrhoeae, or M. genitalium infection).
Despite evidence from epidemiologic and in vitro studies demonstrating a relationship between BV and STI acquisition, only 1
randomized trial of BV therapy has evaluated the effect of BV
treatment on STI incidence. Schwebke et al reported that the incidence of STIs was lower among those who received weekly intravaginal metronidazole gel, compared with standard of care
[10]. Our findings from the PVI trial, combined with those
from Schwebke et al, provide evidence in support of the hypothesis that interventions that improve vaginal health decrease susceptibility to bacterial STIs. Additional clinical trials designed
specifically to assess the effect of vaginal health interventions
on STI outcomes are essential to determine if there is a causal
relationship between BV and an increased risk of STI acquisition.
Such trials should evaluate interventions with demonstrated effectiveness in improving vaginal health (ie, decreasing BV) and
be designed to assess the effectiveness of the intervention on
STI outcomes. If BV increases susceptibility to STIs, this causal
link could warrant shifts in clinical approaches to managing
asymptomatic BV, for which treatment is not currently recommended for nonpregnant women [8]. Interventions that improve
vaginal health could play an important role in decreasing the STI
risk in individual women, as well as informing public health approaches to decrease the STI incidence globally.
Notes
Acknowledgments. We thank the women who participated in this
study; the PVI study team and study sites, for their tireless work on data
and sample collection; FHI 360, for their work on data management and
study operations; and Carolyn Deal, PhD, from the National Institutes of
Health Department of Microbiology and Infectious Disease, for her guidance and support of this work.
J. E. B. and R. S. M. conceptualized the article and analysis
plan. J. E. B. conducted the analysis in collaboration with J. L. and
R. S. M. J. E. B. drafted the initial report, and L. E. M., J. L., and R. S. M.
contributed to the content and revisions. O. A., J. K., J. Schwebke, J. Shafi,
C. R., and E. K. contributed to data collection. All authors contributed to
article content and approved the final manuscript.
Disclaimer. The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes of Health.
Financial support. This work was supported by the National Institute
of Allergy and Infectious Diseases (contract HHSN266200400073C [to the
Preventing Vaginal Infections trial], through the Sexually Transmitted Infections Clinical Trials Group, and grant R01-AI099106 [for C. trachomatis
and N. gonorrhoeae testing]), the American Sexually Transmitted Disease
Association (developmental award for M. genitalium testing), and the National Institutes of Health (grant P30-AI27757 [for infrastructural and logistical support at the Mombasa site], through the University of Washington
Center for AIDS Research).
Potential conflicts of interests. J. E. B. received donated assay reagents
for M. genitalium testing from Hologic/Gen-Probe and honoraria for consulting from Symbiomix. R. S. M. has received honoraria for invited lectures
and consulting, as well as donated study product for the PVI trial, from
Embil Pharmaceutical Company. R. S. M. currently receives research funding from Hologic/Gen-Probe. J. S. has received consultancy payments from
Akesis, Hologic, Symbiomix, and Starpharma and has grants/pending
grants from Akesis, BD Diagnostic, Hologic, Cepheid, Quidel, Symbiomix,
Starpharma, and Viamet. L. E. M. has received donated reagents and test kits
from Hologic/Gen-Probe and honoraria for scientific advisory board membership from Hologic/Gen-Probe and Qiagen. All other authors report no
potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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