Clinical Infectious Diseases

REVIEW ARTICLE

Doxycycline Prophylaxis for Bacterial Sexually

Transmitted Infections

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Juliana S. Grant,1 Chrysovalantis Stafylis,2 Connie Celum,3,4,5 Troy Grennan,6 Bridget Haire,7 John Kaldor,7 Anne F. Luetkemeyer,8 John M. Saunders,9
Jean-Michel Molina,10,11 and Jeffrey D. Klausner2,12,13
1
JSG Health, LLC, Seattle, Washington DC, USA; 2Division of Infectious Diseases, University of California–Los Angeles (UCLA) David Geffen School of Medicine, Los Angeles, California, USA;
3
Department of Global Health, University of Washington, Seattle, Washington DC, USA; 4Department of Medicine, University of Washington, Seattle, Washington DC, USA; 5Department of
Epidemiology, University of Washington, Seattle, Washington DC, USA; 6British Columbia Centre for Disease Control and Division of Infectious Diseases, University of British Columbia, Vancouver,
Canada; 7The Kirby Institute, University of New South Wales, Sydney, Australia; 8Zuckerberg San Francisco General, University of California, San Francisco, California, USA; 9Blood Safety,
Hepatitis, STI, and HIV Division, National Infection Service, Public Health England, London, United Kingdom; 10Department of Infectious Diseases, St-Louis Hospital, University of Paris Diderot,
Paris, France; 11INSERM U944, Paris, France; 12Department of Epidemiology, University of California–Los Angeles (UCLA), Los Angeles, California, USA; and 13Fielding School of Public Health,
University of California–Los Angeles (UCLA), Los Angeles, California, USA

Bacterial sexually transmitted infections (STIs) have been increasing over the past 2 decades in gay, bisexual, and other men who
have sex with men. With the widespread use of early human immunodeficiency virus (HIV) treatment, which virtually eliminates
transmission risk, and the availability of HIV pre-exposure prophylaxis, there have been attitudinal changes regarding HIV infection
with resultant increases in sexual contact and declines in condom use. Doxycycline is used for primary prophylaxis in a number of
infectious diseases. We conducted a state-of-the-art review to examine the current state of research, knowledge gaps, and challenges
around the use of doxycycline prophylaxis to prevent syphilis and other STIs. International academic and government experts met in
March 2019 to frame the initial inquiry, which was supplemented by focused literature searches. Two small short-term randomized
controlled trials examining doxycycline prophylaxis found high efficacy. Five additional clinical studies are underway or in devel-
opment. Studies differed in design, population, outcomes, and safety measures. Doxycycline prophylaxis for bacterial STIs shows
promise. Better and more robust data are needed on efficacy; target population; community acceptability; behavioral risk compen-
sation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness; and risk–benefit.
Keywords. doxycycline; prophylaxis; syphilis; chlamydia; men who have sex with men.

Bacterial sexually transmitted infections (STIs) have been around the use of doxycycline prophylaxis to prevent syphilis,
steadily increasing in gay, bisexual, and other men who have caused by Treponema pallidum (TP), and other bacterial STIs
sex with men (MSM) over the past 2 decades [1–4]. While that such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae
trend started prior to the introduction of human immunode- (NG). International public health and clinical experts from
ficiency virus (HIV) pre-exposure prophylaxis (PrEP) in 2012 academia, government, and community-based organizations
[1, 3], HIV PrEP has been associated with increases in sexual met on 3 March 2019 in Seattle, Washington, to frame the in-
contacts and decreases in condom use with an resultant acceler- itial inquiry, which was then supplemented by focused litera-
ation in the increase of bacterial STIs such as gonorrhea, syph- ture searches to address specific questions of interest. Findings
ilis, and chlamydia [5–8]. However, the increasing adoption of are summarized using the Grading of Recommendations,
HIV PrEP [8] has shown that biomedical interventions for STI Assessment, Development, and Evaluations framework specif-
prevention can be effective, safe, and highly acceptable. ically focusing on the quality of evidence and benefits versus
This state-of-the-art review was conducted to examine harms [9].
the current state of research, knowledge gaps, and challenges

CURRENT EVIDENCE ON DOXYCYCLINE

Received 11 May 2019; editorial decision 26 August 2019; accepted 29 August 2019; published PROPHYLAXIS
online September 1, 2019.
Correspondence: J. D. Klausner, Division of Infectious Disease and Department of Doxycycline is a moderate-spectrum, second-generation tet-
Epidemiology, UCLA David Geffen School of Medicine and Fielding School of Public Health,
racycline that is generally well tolerated [10]. It is rapidly and
10920 Wilshire Blvd, Suite 350, Los Angeles, CA 90025 ([email protected]).
Clinical Infectious Diseases®  2020;70(6):1247–53
almost completely absorbed after oral administration [10].
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases First introduced commercially in the 1960s, doxycycline has
Society of America. This is an Open Access article distributed under the terms of the Creative
been used by millions to manage acne and as primary prophy-
Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/
by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any laxis for scrub typhus [11], leptospirosis [12], malaria [13], and
medium, provided the original work is not altered or transformed in any way, and that the Lyme disease [14]. There are anecdotal reports of doxycycline
work is properly cited. For commercial re-use, please contact [email protected]
DOI: 10.1093/cid/ciz866 used for syphilis prophylaxis among US and Australian military

Doxycycline Prophylaxis for STIs • cid 2020:70 (15 March) • 1247

personnel during the Vietnam War. Doxycycline is a first-line taking Doxy PEP had lower STI incidence (hazard ratio, 0.57;
agent for treatment of chlamydia and an alternative regimen for P = .014). Chlamydia trachomatis and syphilis diagnoses were
syphilis [10, 15]. significantly lower in the intervention arm, with a relative re-
Several studies examined doxycycline prophylaxis for STI duction of 70–73% in the intention-to-treat analysis. Neisseria
prevention (Table 1). In a small, open-label pilot study, 30 MSM gonorrhoeae diagnoses did not differ except for fewer urethral
living with HIV with prior syphilis were randomized 1:1 to daily cases in those using Doxy PEP. Four of 9 NG-positive cultures,
doxycycline 100 mg as pre-exposure prophylaxis (Doxy PrEP) all from the control arm, had high-level tetracycline resistance

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for 48 weeks versus a financial incentive–based behavioral in- consistent with the French background rate [10]. Eighty-two
tervention [16]. There was a 73% reduction (P = .02) in syphilis, percent (n = 31) of participants with NG detected by nucleic
NG, or CT in the Doxy PrEP group compared with the control acid amplification testing had genotypic markers of tetracy-
group. Most intervention-arm participants maintained blood cline resistance; there was no difference between study arms
doxycycline levels of greater than 1 μg/mL. Reported sexual be- (P = .4). All CT culture isolates (n = 5) were doxycycline suscep-
haviors were similar in both groups. tible. Adherence was high in the Doxy PEP arm; 63% had dox-
An open-label extension of the French national HIV re- ycycline detected in at least 1 plasma specimen. Twenty-nine
search agency (France Recherche Nord & sud Sida-hiv hépatites (21.5%) Doxy PEP patients discontinued doxycycline, 8 for
[ANRS]) Intervention Préventive de l’Exposition aux Risques gastrointestinal side effects. Sexual behaviors did not generally
avec et pour les Gays (IPERGAY) HIV-prevention study con- differ between the 2 groups.
tinued participant access to HIV PrEP and examined doxy- While not direct clinical evidence, a modeling study examining
cycline postexposure prophylaxis (Doxy PEP) in MSM and the impact of Doxy PrEP on syphilis among Australian MSM esti-
transgender women without HIV [17]. Participants (n = 232) mated that if 50% of MSM used Doxy PrEP and it was 70% effec-
were randomly assigned 1:1 to the intervention—doxycy- tive syphilis would decrease by 50% after 12 months and 85% after
cline 200 mg within 24–72 hours of condomless sexual en- 10 years [18]. The authors predicted a similar effect if only 50% of men
counters up to 3 times per week—or to no prophylaxis. Those with more than 20 partners in 6 months were taking doxycycline.

Table 1. Key Characteristics of Completed Studies on Doxycycline Prophylaxis for Sexually Transmitted Infections

Study Population
Study, First Author Sample and Inclusion
[Reference] Design Size Intervention Criteria Duration Findings

Bolan [16] Open-label RCT; 30 Daily doxycycline MSM living with 48 weeks Diagnosis of any bacterial STI at any
patients randomized hyclate, 100 mg HIV infection; 2 site: odds ratio 0.27 (0.09–0.83),
1:1 to interven- tablet or more treated P = .02; no significant differences
tion and standard syphilis diag- in sex behaviors at baseline or fol-
of care noses since HIV low-up.
diagnosis One patient discontinued doxycycline
due to GERD.
ANRS IPERGAY Open-label RCT; 232 Doxycycline hyclate, MSM and trans- Median follow-up, Diagnosis of any bacterial STI at any
Doxy PEP study, patients ran- 200 mg tablet, gender women 8.7 months site: hazard ratio = 0.57 (0.13–0.62),
Molina [17] domized 1:1 to single dose within without HIV on P = .014. No substantive difference
intervention and 24–72 hours post– HIV PrEP having in sexual behaviors at baseline or
no prophylaxis condomless sexual condomless sex during study; 32 patients discon-
encounter; max- with men tinued doxycycline, 8 for gastro-
imum 3/week intestinal side effects. Remainder
discontinued for multiple reasons
with no discernable pattern.
Wilson [18] Model of sexual NA Daily doxycycline, 100 MSM NA Assuming 50% adoption and 70%
behavior mg efficacy, ~50% reduction in syphilis
after 12 months and 85% reduction
after 10 years. Similar effect seen
if only MSM with >10 partners in
6 months receiving intervention.
Wilson [18] Survey and focus 2095 NA MSM NA 52.7% (95% confidence interval,
groups using 50.6–54.8%) very/slightly likely to
respondent-driven use doxycycline to prevent syphilis
and convenience in themselves; 75.8% (74.0–77.6%)
sampling very/slightly likely to use doxycy-
cline to help control syphilis in MSM
community.
Survey findings supported by focus
groups.

Abbreviations: ANRS IPERGAY, France Recherche Nord & sud SIDA-HIV hépatites Intervention Préventive de l’Exposition aux Risques avec et pour les Gays; Doxy, doxycycline; GERD,
gastroesophageal reflux disease; HIV, human immunodeficiency virus; MSM, men who have sex with men; NA, not applicable; PEP, postexposure prophylaxis; PrEP, pre-exposure prophy-
laxis for HIV; RCT, randomized controlled trial; STI, sexually transmitted infection.

1248 • cid 2020:70 (15 March) • Grant et al

Table 2. Key Characteristics of Studies in Progress or Development on Doxycycline Prophylaxis for Sexually Transmitted Infections, March 2019

Sample Duration,
Study, PI Design Size Intervention Study Population, Inclusion Criteria mo Endpoints

DuDHS, Grennan Immediate/deferred 50 Daily doxycycline MSM on HIV PrEP; condomless sex in 6/12 Acceptability, adher-
initiation single-blind hyclate, 100 mg last 6 months, and syphilis diagnosed ence, and tolera-
RCT; patients ran- and treated within last 3 years bility; resistance in
domized 1:1 to inter- oral flora; change in
vention and deferred sexual activity; STI

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intervention diagnosis
DaDHS, Grennan Single-blind RCT; pa- 52 Daily doxycycline MSM living with HIV infection; 12 Adherence and tolera-
tients randomized hyclate, 100 mg condomless sex in last 6 months, bility; resistance in
1:1 to intervention and syphilis diagnosed and treated oral flora; change in
and placebo within last 3 years sexual activity; bacte-
rial STI diagnosis
Syphilaxis, Kaldor Nonrandomized single- 350 Daily doxycycline MSM living with HIV and without HIV 12 Use and acceptability;
arm trial; before– monohydrate and transgender persons reporting NG, CT, and syphilis
after comparisons tablet, 100 mg recent sex with men; diagnosed diagnosis; rectal
using medical syphilis in prior 12 months, or any STI and oropharyngeal
records; STI sur- in last 12 months and syphilis in last microbiome substudy
veillance data com- 24 months; at least 2 episodes of STI on antimicrobial re-
paring study patients screening in prior 12 months sistance (n = 100)
with unenrolled
MSM with matching
risk profiles
ANRS Previnir RCT open-label; pa- 700 Doxycycline mono- MSM already enrolled in the ANRS 18 CT, NG, and syphilis
PrEP tients randomized hydrate, 200 mg, Prevenir PrEP trial with a history of incidence; culture
study, Molina 2:1 to intervention single dose recent STI and molecular-based
Doxy PEP or no post–condomless resistance testing;
PEP combined with sexual encounter rectal and oral
RCT on impact of microbiome substudy
meningococcal type on antimicrobial re-
B vaccination on NG sistance
incidence (randomi-
zation 1:1)
Doxy PEP study, Open-label RCT; pa- 780 Doxycycline hyclate MSM living with HIV infection and MSM 12 NG, CT, and syphilis
Celum and tients randomized to delayed release, on HIV PrEP; 1 or more bacterial STI diagnosis; culture
Luetkemeyer 2:1 to intervention 200 mg, single and condomless sex with 1 or more and molecular-based
and no prophylaxis dose within male partners in past year resistance testing;
24–72 hours commensal flora
post–condomless and gut microbiome
sexual encounter, resistance testing
up to daily use
Abbreviations: ANRS, France Recherche Nord & sud SIDA-HIV hépatites; CT, Chlamydia trachomatis; DaDHS, Daily Doxycycline in HIV+ for Syphilis PrEP; Doxy, doxycycline; DuDHS, Dual
Daily HIV and Syphilis PrEP; HIV, human immunodeficiency virus; MSM, men who have sex with men; NG, Neisseria gonorrhoeae; PEP, postexposure prophylaxis; PI, principal investigator;
PrEP, pre-exposure prophylaxis; RCT, randomized controlled trial; STI, sexually transmitted infection.

STUDIES UNDERWAY OR IN DEVELOPMENT delayed arm. No serious adverse events have occurred, although
The meeting participants discussed 5 studies underway or in participants in the treatment arm have reported more nausea.
development on Doxy PEP/PrEP (Table 2). A pilot study, the The Daily Doxycycline in HIV+ for Syphilis PrEP (DaDHS)
Dual Daily HIV and Syphilis PrEP (DuDHS) Study in Canada, Study is examining Doxy PrEP in MSM living with HIV; 52 par-
is examining concurrent daily HIV PrEP and Doxy PrEP in ticipants with a prior history of syphilis will be randomized 1:1
MSM without HIV. The study will randomize 50 participants to daily doxycycline 100 mg or placebo.
1:1 to immediate Doxy PrEP versus delayed initiation after The Syphilaxis Study in Australia will be a single-arm study of
6 months; all participants will receive 1 year of HIV PrEP. The Doxy PrEP in 350 MSM and transgender persons reporting re-
primary objective is to examine the acceptability, adherence, cent sex with men. MSM with a history of regular STI testing are
and tolerability of daily HIV PrEP and Doxy PrEP. The study eligible if they are living with HIV or do not have HIV and are
will also evaluate STI incidence, sexual behavior, tetracycline- using HIV PrEP. The study will use medical records to measure
class bacterial resistance through culture of the oropharynx and before–after frequencies of STI diagnoses and an existing STI
nares, and an evaluation of the rectal microbiome. As of March surveillance database to compare frequencies between study
2019, investigators have not detected any STIs in the patients re- participants and unenrolled MSM. Participants will record dox-
ceiving Doxy PrEP in contrast to 3 patients with rectal CT in the ycycline use daily and complete quarterly questionnaires. The

Doxycycline Prophylaxis for STIs • cid 2020:70 (15 March) • 1249

primary goals are to measure acceptability of daily doxycycline acts were protected. Studies underway will lead to more pre-
and effectiveness in preventing syphilis, NG, and CT. cise measures of overall efficacy and efficacy for specific sexual
In France, a substudy within the large ANRS Prevenir PrEP behaviors. Those measures are important to inform clinical de-
cohort (n = 3000) [19] will use a randomized, open-label, fac- cision making, cost-effectiveness analyses, community educa-
torial design to examine the efficacy of meningococcal type B tion, and patient counseling.
vaccine in preventing NG infection and the use of Doxy PEP
200 mg to prevent chlamydia and syphilis in participants with a Population of Focus

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prior STI diagnosis in the past 18 months. Seven hundred parti- Public health experts have long promoted controlling STIs in
cipants will be randomized 2:1 to Doxy PEP or no PEP and 1:1 a core population of individuals with a high number of sexual
to meningococcal type B vaccine or no vaccine. contacts as an approach to reduce STIs in the general population
A US study examining Doxy PEP effectiveness and safety/tol- [23, 24]. Modeling based on Australian parameters [18] sug-
erability will enroll 780 MSM and male-to-female transgender gests that focusing on MSM with higher numbers of sex part-
individuals (390 living with HIV and 390 without HIV using ners (>20 partners in 6 months) would be almost as effective
HIV PrEP) who had 1 or more bacterial STI(s) and 1 or more as broader Doxy PrEP use. Current and planned studies have
episode(s) of condomless sexual contact with 1 or more male generally focused on MSM at higher risk of STIs and/or HIV in-
partner(s) in the previous year. The trial will be open-label with fection, but criteria vary and sample sizes may not be sufficient
2:1 randomization to Doxy PEP 200 mg post–condomless sexual to stratify results for subpopulations with more elevated risk.
contact, up to daily use, versus standard of care with 12 months Additional modeling studies or pooled analyses may be useful
of follow-up. All positive NG cultures will undergo tetracycline to identify the characteristics of populations most suitable for
susceptibility testing. Specimens from patients diagnosed with maximizing the impact of doxycycline prophylaxis.
syphilis or CT will undergo molecular tetracycline resistance
evaluation using a novel clustered regularly interspaced short Benefits and Harms
Safety
palindromic repeats/Cas9 targeted sequencing technique [20].
Adults generally tolerate doxycycline well [10]. Studies dem-
This will provide a broad-reaching, rapid-throughput method
onstrate the most commonly reported side effects are related
for assessing tetracycline and other antimicrobial resistance
to gastrointestinal (<1–55% of patients) and skin (<1–42% of
genes. Participants will have nasopharyngeal swabs cultured
patients), including photosensitivity (6–42%), toxicity over
to assess for tetracycline susceptibility in Staphylococcus au-
7 days to 6 months of use [10]. The most severe gastrointestinal
reus and Neisseria spp. and rectal swabs and stool samples for
effects are esophageal erosion and ulceration; these are most
metagenomic tests to determine predominant species, species
commonly associated with uncoated doxycycline hyclate [25].
diversity, and changes in the presence of tetracycline resistance
Infrequent, more serious side effects in adults, including al-
genes over time.
lergic reactions, exacerbation of systemic lupus erythematosus,
anemia, hemolytic anemia, thrombocytopenia, eosinophilia,
KNOWLEDGE GAPS AND CHALLENGES
neutropenia, intracranial hypertension, and tooth staining, are
While the studies described above help address some of the rare [25]. Most serious adverse effects resolve with discontin-
knowledge gaps around Doxy PEP/PrEP, there remain multiple uation of doxycycline [25]. Despite the known side effects, in
areas for further research, particularly around efficacy and po- clinical trials discontinuation due to side effects has been un-
tential benefits and harms. common [13, 16, 17, 26].
Clinicians routinely prescribe low doses (40–100 mg daily) of
Quality of the Evidence doxycycline for weeks to months for acne and rosacea [25] and
Efficacy months to years for malaria prophylaxis [13]. Multiple studies
Studies on Doxy PEP/PrEP used 2 doxycycline dose/reg- on side effects among patients using doxycycline for malaria
imen options: 100 mg daily [16] or 200 mg single-dose prophylaxis have been contradictory or insufficient to draw
post–condomless sex event [17]. Investigators selected those clear conclusions [13]. Researchers have studied prolonged
regimens from experience with doxycycline prophylaxis in doxycycline use (3–18 months) for the management of abdom-
other infectious diseases [12, 14] and the minimum inhibitory inal aortic aneurysm. No serious adverse reactions were seen in
concentration (MIC) of TP [21]. The efficacy of doxycycline those studies and fewer than 10% of patients withdrew because
for pre- or postexposure prophylaxis has yet to be definitively of medication side effects [26–29].
determined. While the 2 randomized controlled trials (RCTs)
conducted to date had similar levels of efficacy (~70%), the es- Formulation, Tolerability, and Regimen
timated effect sizes were imprecise because of modest sample Doxycycline monohydrate and doxycycline hyclate are the most
sizes [16, 17, 22]. Additionally, it is unknown which specific sex commonly used formulations of doxycycline. Due to the pH at

1250 • cid 2020:70 (15 March) • Grant et al

which they are soluble, esophageal side effects may be less fre- has been documented to occur due to a single point mutation
quent with doxycycline monohydrate or enteric-coated doxycy- [40], suggesting the potential for tetracycline resistance [41].
cline hyclate compared with uncoated doxycycline hyclate [30]. Antimicrobial resistance in Mycoplasma genitalium (MG),
Since the formulation of doxycycline used may impact side ef- a frequent cause of nongonococcal urethritis in men, is also a
fects and patient adherence, this should be tracked closely in growing concern [42, 43]. Even though tetracyclines have low
future RCTs. efficacy against MG [15], doxycycline is a recommended alter-
Patient preference is another major consideration. A small native regimen [15] because of emerging resistance to first-line

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qualitative study in Australia (N = 13) found that participants treatments. In a substudy of the ANRS IPERGAY doxycycline
have a strong preference for daily dosing. Patients preferences extension, 11% of the 210 participants tested positive for MG
may vary by HIV infection status, use of HIV PrEP, and how at baseline and 11 participants acquired MG during the study
individuals use HIV PrEP (eg, daily or intermittently). [43]. Azithromycin and fluoroquinolone resistance was iden-
tified in 70% and 15%, respectively, of tested specimens [43].
Antimicrobial Resistance Broad doxycycline use in populations with high prevalence
Concern around antimicrobial resistance has been raised by rates of MG could decrease treatment options for that bacte-
some clinicians and public health organizations, along with a rium. Mycoplasma genitalium prevalence and antibiotic suscep-
call for more research in this area [31]. In the United States, tibilities should be examined in future studies.
23.1% of NG isolates tested in 2017 were resistant to tetracy- Finally, Doxy PEP/PrEP could contribute to development
cline [1]; NG resistance to tetracycline is higher in some parts of doxycycline resistance in commensal organisms, including
of Europe (France: 45%; England: 49%) [10, 32]. Additionally, those with the potential to transmit resistance. Studies of mil-
gonococcal antimicrobial resistance is frequently higher among itary members deployed overseas taking doxycycline for ma-
MSM [1, 32], the population most likely to use Doxy PEP/PrEP. laria prophylaxis have found conflicting data on the impact
However, given the existing high rates of tetracycline resistance of doxycycline prophylaxis on antimicrobial resistance in
in NG and the fact that doxycycline is not recommended for oropharyngeal and intestinal commensal organisms [44–46].
treatment, another perspective may be that the additional con- Further study is needed. While it is possible to evaluate the im-
tribution of prophylactic use to NG resistance in this context is pact of doxycycline on oral and rectal flora by examining the
negligible. microbiome and resistome in these areas, there are no standard
There are no established standards for identifying or meas- guidelines for interpreting findings.
uring doxycycline resistance in NG, CT, or TP via culture or
molecular techniques, although investigators have developed Community Acceptability and Perceptions
methods for research purposes and most clinicians apply tetra- Multiple surveys have demonstrated that doxycycline prophy-
cycline susceptibility data for NG to doxycycline [33–35]. laxis is acceptable to MSM. In an online survey of 2095 Australian
Treatment failure in CT has been reported in 5–23% of per- MSM, 53% indicated they would be likely to take doxycycline to
sons [36], although these studies did not test for resistance and prevent syphilis and 76% indicated they would take doxycycline
the causes of treatment failure are unclear. Treatment failure in to reduce syphilis in the community [18]. Among 1301 users
patients with CT has been associated with a range of in vitro dox- of a US social-networking app for MSM, 84% were interested
ycycline MICs of more than 0.125 μg/mL to more than 4.0 μg/ in trying Doxy PEP [47]. Interest was higher among African-
mL [33, 37]; however, there is not a strict correlation between American and Latino/a respondents [47]. At a joint Australia–
treatment failure and tested MIC [33] so the clinical relevance New Zealand HIV/STI scientific meeting of clinical and public
of these findings are unclear. Several small population-level health experts in 2015, 52% of 63 providers felt that the benefits
studies in communities with high background doxycycline use of doxycycline prophylaxis outweighed the risks, although 88%
or subsequent to mass-treatment programs for trachoma did had some concerns about antimicrobial resistance.
not find evidence of doxycycline resistance in CT [36]. Some MSM in North America and Europe may already be
Two studies have evaluated tetracycline resistance in TP. In using doxycycline for STI prophylaxis. In a survey of MSM
China, molecular typing of TP from 438 case-patients [34] with taking HIV PrEP in the United Kingdom [48], 6 of 106 respond-
syphilis found no evidence of a mutation in the 16S rRNA gene ents reported taking doxycycline to prevent STIs in the previous
that is associated with tetracycline resistance in other bacterial 6 months. In the ANRS IPERGAY Doxy PEP study [17] 3–13%
species. A similar study of 53 case-patients in Italy [38] also did of participants in the placebo group had detectable doxycycline
not identify any doxycycline resistance mutations. Complete ge- blood levels at each study visit. Doxycycline is also frequently
nome sequencing of TP [39] has not found genetic elements as- available through online companies selling HIV PrEP [31].
sociated with gene-transfer mechanisms. That suggests that TP Researchers and study participants have expressed concern
is less likely than other bacteria to develop plasmid-mediated about the potential for confusion between Doxy PEP/PrEP and
antimicrobial resistance. However, macrolide resistance in TP HIV PrEP. Both medications can be used daily or intermittently.

Doxycycline Prophylaxis for STIs • cid 2020:70 (15 March) • 1251

Individuals living with HIV may believe themselves to be in-  Clinical efficacy: Quantifying clinical efficacy in a variety of populations is needed.
 Dosing strategies: Daily and post-exposure/event-driven dosing is being studied.
eligible for Doxy PEP/PrEP. Individuals without HIV may not Other options, such as weekly dosing, should be investigated.
 Core group focused intervention: Modeling and analyses of pooled study data are
understand that HIV PrEP does not protect them against STIs needed to identify the populations most suitable for maximizing the impact of
doxycycline prophylaxis.
and Doxy PEP/PrEP does not protect them from HIV. Effective  Formulation: Clear information on the frequency of side effects for different
educational campaigns, designed using evidence from ongoing doxycycline formulations is needed. Direct comparisons using randomized clinical
trials may be appropriate. Further long-term studies on side effects are also needed.
and future studies, will be critical to address those concerns.  Educational efforts: Prior to broad implementation, effective educational campaigns
are needed to ensure that high-risk populations clearly understand the difference
between HIV PrEP and Doxy PEP/PrEP

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 Risk compensation: Ongoing monitoring for risk compensation in all trials is critical.
Risk Compensation  Resistance monitoring: All studies should robustly investigate development of
resistance in bacterial STIs as well as commensal organisms. Standardized laboratory
Investigators have documented decreased condom use among methods for defining and monitoring doxycycline resistance in STIs are needed.
Cost-effectiveness: Cost-effectiveness analyses are needed to better understand the
MSM using HIV PrEP [8]. While reports from completed Doxy 
utility of Doxy PEP/PrEP.
PEP/PrEP trials have not identified similar changes in risk be-
havior [16, 17], findings from the ongoing Canadian DuDHS Figure 1. Recommendations for research activities. Abbreviations: Doxy, doxy-
study suggest some risk compensation might occur. Notably, cycline; HIV, human immunodeficiency virus; PEP, postexposure prophylaxis; PrEP,
risk compensation among people taking HIV PrEP was not pre-exposure prophylaxis; STI, sexually transmitted infection.

identified in the initial placebo-controlled trials but only be-

came evident in later uncontrolled trials [8]. and modeling studies that consider different scenarios and in-
dividual- versus population-level impacts of Doxy PEP/PrEP
Risk–Benefit and Cost-effectiveness
are needed to guide conclusions around the appropriateness of
While the benefits of HIV PREP as a way to prevent a life-
Doxy PEP/PrEP to prevent bacterial STIs.
threatening infection are clear, the risk-balance of STI preven-
tion may be more uncertain. As Golden and Handsfield [22] Notes
suggest, a key issue to consider is which benefits of Doxy PEP/ Acknowledgments. The authors thank Robert Bolan and Matt Golden for
PrEP are most important to prioritize. While STI treatment has their expertise and assistance in developing this manuscript. We also thank
the attendees of the Doxycycline for Prevention of Syphilis in High-Risk
significant personal and financial costs, and STIs can cause se-
Populations preconference leadership meeting for CROI 2019 who contrib-
rious sequelae in men (eg, blindness and hearing loss due to uted to a useful and insightful discussion: Cherie Blair, Robert Bolan, David
syphilis), much of the direct STI morbidity is in women (infer- Burns, Phillip Chan, Vincent Cornelisse, Carlos Del Rio, Julie Dombrowski,
tility and adverse pregnancy outcomes). Primarily using Doxy Deborah Donnell, Richard Gilson, Matt Golden, Rebecca Guy, Elske
Hoornenborg, Jeanne Marrazzo, Tarek Mikati, Sheldon Morris, Vincent
PEP/PrEP in MSM, a population at high risk of bacterial STIs, Ofori, and Darrell Tan.
might have relatively limited impact on reproductive health Financial support. This work was supported by Team Klausner Saving
outcomes at the population level. The question of which bene- Lives, University of California Los Angeles Center for AIDS Research
(grant number 5P30 AI028697) and the National Institute of Allergy and
fits to focus on will also directly impact the cost-effectiveness
Infectious Diseases (NIAID grant number 1R01AI139265).
of Doxy PEP/PrEP as the number of people who would need to Potential conflicts of interest. A. F. L. has received grants from ViiV
receive treatment to avert a negative outcome will vary substan- Healthcare Limited. J-M. M. has received personal fees from Gilead
Sciences, Inc, Merck & Co., ViiV Healthcare Limited, Bristol-Myers Squibb,
tially depending on the outcome selected [22].
and Teva Pharmaceutical Industries and grants from Gilead Sciences, Inc.
The other authors report no potential conflicts. All authors have submitted
CONCLUSIONS the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts
that the editors consider relevant to the content of the manuscript have been
Based on our review of the current evidence and studies un- disclosed.
derway, doxycycline prophylaxis for bacterial STIs shows
promise. However, there are several research priorities that References
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