Doxycycline prophylaxis for bacterial
sexually transmitted infections - Review
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This state-of-the-art review was conducted to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis, caused by Treponema pallidum (TP), and other bacterial STIs such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG).
Summary: Sexually transmitted infections have been increasing among men who have sex with men. Doxycycline prophylaxis for syphilis and chlamydia has been effective in initial trials. Future research should focus on populations with high incidence/morbidity, dose and regimen, and antimicrobial resistance.
While the studies described above help address some of the knowledge gaps around Doxy PEP/PrEP, there remain multiple areas for further research particularly around efficacy, and potential benefits and harms.
Clinical Infectious Diseases 01 September 2019
Juliana S. Grant, JSG Health, LLC, Seattle, Washington, United States Chrysovalantis Stafylis, Division of Infectious Diseases, UCLA David Geffen School of Medicine, Los Angeles, California, United States
Connie Celum, Departments of Global Health, Medicine, and Epidemiology, University of Washington, Seattle, Washington, United States
Troy Grennan, British Columbia Centre for Disease Control and Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia, Canada
Bridget Haire, The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
John Kaldor, The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
Anne F. Luetkemeyer, Zuckerberg San Francisco General, University of California, San Francisco, San Francisco, California, United States
John M. Saunders, Blood Safety, Hepatitis, STI and HIV Division, National Infection Service, Public Health England, London, United Kingdom
Jean-Michel Molina, Department of Infectious Diseases, St-Louis Hospital, University of Paris Diderot, and INSERM U944, Paris, France
Bacterial sexually transmitted infections (STI) have been increasing over the past two decades in gay, bisexual, and other men who have sex with men (MSM). With the widespread use of early 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-control trials examining doxycycline prophylaxis have found high efficacy. Five additional clinical studies are underway or in development. 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 compensation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness and risk-benefit.
Based on our review of the current evidence and studies underway, doxycycline prophylaxis for bacterial STIs shows promise. However, there are several research priorities that need to be addressed before it be adopted broadly.(Figure) In addition to increasing the evidence base on the efficacy of Doxy PEP/PrEP, researchers should carefully consider which populations to focus on, doxycycline formulation and regimen, and ensuring that findings can be translated to real-world implementation. Pooled analyses across studies may be helpful in examining issues such as identifying sub-populations most likely to benefit from Doxy PEP/PrEP. There is also a clear and immediate need to develop consistent laboratory methods for evaluating doxycycline resistance in NG, CT, TP, and MG, as well as other common pathogens like Staphylococcus aureus and Streptococcus pneumonia. and broader guidance on how to interpret and use microbiome and resistome data. Finally, cost-effectiveness and modeling studies that consider different scenarios around the most suitable population to focus on and individual versus population-level impacts of Doxy PEP/PrEP are needed to guide conclusions around the appropriateness of Doxy PEP/PrEP to prevent bacterial STIs.
Bacterial sexually transmitted infections (STI) have been steadily increasing in gay, bisexual, and other men who have sex with men (MSM) over the past two decades.[1-4]. While that trend started prior to the introduction of human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) in 2012,[1, 3] HIV PrEP has been associated with increases in sexual contacts and decreases in condom use with an resultant acceleration in the increase of bacterial STIs like gonorrhea, syphilis and chlamydia.[5-8] However, the increasing adoption of HIV PrEP has shown that biomedical interventions for STI prevention can be effective, safe, and highly acceptable.
This state-of-the-art review was conducted to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis, caused by Treponema pallidum (TP), and other bacterial STIs such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). International public health and clinical experts from academia, government, and community-based organizations met on March 3, 2019, in Seattle, Washington to frame the initial inquiry which was then supplemented by focused literature searches to address specific questions of interest. Findings are summarized using the Grading of Recommendations, Assessment, Development and Evaluations framework specifically focusing on the quality of evidence and benefits versus harms.
2. Current evidence on doxycycline prophylaxis
Doxycycline is a moderate-spectrum second-generation tetracycline that is generally well tolerated. It is rapidly and almost completely absorbed after oral administration. First introduced commercially in the 1960s, doxycycline has been used by millions to manage acne and as primary prophylaxis for scrub typhus, leptospirosis, malaria, and Lyme disease. There are anecdotal reports of doxycycline used for syphilis prophylaxis among U.S. and Australian military personnel during the Vietnam War. Doxycycline is a first-line agent for treatment of chlamydia and an alternative regimen for syphilis.[10, 15]
Several studies examined doxycycline prophylaxis for STI prevention.(Table 1) In a small open-label pilot study, 30 HIV-infected MSM with prior syphilis were randomized 1:1 to daily doxycycline 100 mg as pre-exposure prophylaxis (Doxy PrEP) for 48 weeks versus a financial incentive-based behavioral intervention. There was a 73% reduction (p = .02) in syphilis, GC, or CT in the Doxy PrEP group compared to the control group. Most intervention-arm participants maintained blood doxycycline levels >1 μg/mL. Reported sexual behaviors were similar in both groups.
An open-label extension of the French national HIV research agency (ANRS) IPERGAY HIV prevention study continued participant access to HIV PrEP and examined doxycycline post-exposure prophylaxis (Doxy PEP) in HIV-uninfected MSM and transgender women. Participants (n=232) were randomly assigned 1:1 to the intervention, doxycycline 200 mg within 24-72 hours of condomless sexual encounters up to three times per week, or to no prophylaxis. Those taking Doxy PEP had lower STI incidence (hazard ratio = 0.57, p = .014). CT and syphilis diagnoses were significantly lower in the intervention arm with a relative reduction of 70-73% in the intention-to-treat analysis. NG diagnoses did not differ except for fewer urethral cases in those using Doxy PEP. Four of nine NG-positive cultures, all from the control arm, had high-level tetracycline resistance consistent with the French background rate. Eighty-two percent (n=31) of participants with NG detected by nucleic acid amplification testing had genotypic markers of tetracycline resistance; there was no difference between study arms (p = .4). All CT culture isolates (n=5) were doxycycline-susceptible. Adherence was high in the Doxy PEP arm; 63% had doxycycline detected in at least one plasma specimen. Twenty-nine (21.5%) Doxy PEP patients discontinued doxycycline, eight for gastrointestinal side effects. Sexual behaviors did not generally differ between the two groups.
While not direct clinical evidence, a modeling study examining the impact of Doxy PrEP on syphilis among Australian MSM estimated that if 50% of MSM used Doxy PrEP and it was 70% effective, syphilis would decrease by 50% after 12 months and 85% after 10 years. The authors predicted a similar effect if only 50% of men with > 20 partners in six months were taking doxycycline.
3. Studies underway or in development
The meeting participants discussed five studies underway or in development on Doxy PEP/PrEP.(Table 2) A pilot study of Dual Daily HIV and Syphilis PrEP (The DuDHS Study) in Canada is examining concurrent daily HIV PrEP and Doxy PrEP in HIV-uninfected MSM. The study will randomize 50 participants 1:1 to immediate Doxy PrEP versus delayed initiation after 6 months; all participants will receive one year of HIV PrEP. The primary objective is to examine the acceptability, adherence, and tolerability of daily HIV PrEP and Doxy PrEP. The study will also evaluate STI incidence, sexual behavior, tetracycline-class bacterial resistance through culture of the oropharynx and nares, and an evaluation of the rectal microbiome. As of March 2019, investigators have not detected any STIs in the patients on Doxy PrEP in contrast to three rectal CT cases in the delayed arm. No serious adverse events have occurred, although participants in the treatment arm have reported more nausea. The Daily Doxycycline in HIV+ for Syphilis PrEP (The DaDHS Study) is examining Doxy PrEP in HIV-infected MSM; 52 participants with a prior history of syphilis will be randomized 1:1 to daily doxycycline 100 mg or placebo.
The Syphilaxis study in Australia will be a single-arm study of Doxy PrEP in 350 MSM and transgender persons reporting recent sex with men. Both HIV-infected and HIV-uninfected HIV PrEP users with a history of regular STI testing are eligible. The study will use medical records to measure before-after frequencies of STI diagnoses and an existing STI surveillance database to compare frequencies between study participants and unenrolled MSM. Participants will record doxycycline use daily and complete quarterly questionnaires. The primary goals are to measure acceptability of daily doxycycline and effectiveness in preventing syphilis, NG, and CT.
In France, a sub-study within the large ANRS Prevenir PrEP cohort (n=3,000)  will use a randomized open-label factorial design to examine the efficacy of meningococcal type B vaccine in preventing NG infection and the use of Doxy PEP 200 mg to prevent chlamydia and syphilis in participants with a prior STI diagnosis in the past 18 months. Seven hundred participants will be randomized 2:1 to Doxy PEP or no PEP, and 1:1 to meningoccal type B vaccine or no vaccine.
A U.S. study examining Doxy PEP effectiveness and safety/tolerability will enroll 780 MSM and male-to-female transgender individuals (390 HIV-infected and 390 HIV-uninfected using HIV PrEP) who had ≥1 bacterial STI(s) and ≥1 episode(s) of condomless sexual contact with ≥1 male partner(s) in the previous year. The trial will be open-label with 2:1 randomization to Doxy PEP 200 mg post-condomless sexual contact, up to daily use, versus standard of care with 12 months follow-up. All positive NG cultures will undergo tetracycline susceptibility testing. Specimens from patients diagnosed with syphilis or CT will undergo molecular tetracycline resistance evaluation using a novel CRISPR/Cas9 targeted sequencing technique. That will provide a broad reaching, rapid throughput methodology for assessing tetracycline and other antimicrobial resistance genes. Participants will have nasopharyngeal swabs cultured to assess for tetracycline susceptibility in Staphylococcus aureus and Neisseria spp., and rectal swabs and stool samples for metagenomic tests to determine predominant species, species diversity, and changes in the presence of tetracycline resistance genes over time.
4. Knowledge gaps and challenges
While the studies described above help address some of the knowledge gaps around Doxy PEP/PrEP, there remain multiple areas for further research particularly around efficacy, and potential benefits and harms.
4.2. Benefits and harms
Adults generally tolerate doxycycline well. Studies demonstrate the most commonly-reported side effects are related to gastrointestinal (<1%-55% of patients) and skin (<1%-42% of patients), including photosensitivity (6-42%), toxicity over 7 days-6 months of use. The most severe gastrointestinal effects are esophageal erosion and ulceration; these are most commonly associated with uncoated doxycycline hyclate. Infrequent more serious side effects in adults including allergic reactions, exacerbation of systemic lupus erythematosus, anemia, hemolytic anemia, thrombocytopenia, eosinophilia, neutropenia, intracranial hypertension, and tooth staining are rare. Most serious adverse effects resolve with discontinuation of doxycycline. Despite the known side effects, in clinical trials discontinuation due to side effects has been uncommon.[13, 16, 17, 26]
Clinicians routinely prescribe low doses (40-100 mg daily) of doxycycline for weeks to months for acne and rosacea and months to years for malaria prophylaxis. Multiple studies on side effects among patients using doxycycline for malaria prophylaxis have been contradictory or insufficient to draw clear conclusions. Researchers have studied prolonged doxycycline use (3-18 months) for the management of abdominal aortic aneurysm. No serious adverse reactions were seen in those studies and <10% of patients withdrew because of medication side effects.[26-29]
4.2.2. Formulation, tolerability, and regimen
Doxycycline monohydrate and doxycycline hyclate are the most commonly used formulations of doxycycline. Due to the pH at which they are soluble, esophageal side effects may be less frequent with doxycycline monohydrate or enteric-coated doxycycline hyclate compared to un-coated doxycycline hyclate. Since the formulation of doxycycline used may impact side effects and patient adherence, this should be tracked closely in future RCTs.
Patient preference is another major consideration. A small qualitative study in Australia (n=13) found that participants have a strong preference for daily dosing. Patients preferences may vary by HIV infection status, and use of HIV PrEP and how individuals use HIV PrEP (e.g., daily or intermittent).
4.2.3. Antimicrobial resistance
Concern around antimicrobial resistance has been raised by some clinicians and public health organizations, along with a call for more research in this area. In the U.S., 23.1% of NG isolates tested in 2017 were resistant to tetracycline; NG resistance to tetracycline is higher in some parts of Europe (France: 45%; England: 49%).[10, 32] Additionally, gonococcal antimicrobial resistance is frequently higher among MSM,[1, 32] the population most likely to use Doxy PEP/PrEP. However. given the existing high rates of tetracycline resistance in NG and the fact that doxycycline is not recommended for treatment, another perspective may be that the additional contribution of prophylactic use to NG resistance in this context is negligible.
There are no established standards for identifying or measuring doxycycline resistance in NG, CT, or TP via culture or molecular techniques, although investigators have developed methods for research purposes and most clinicians apply tetracycline susceptibility data for NG to doxycycline.[33-35]
Treatment failure in CT has been reported in 5-23% of persons, although these studies did not test for resistance and the causes of treatment failure are unclear.
Treatment failure in patients with CT has been associated with a range of in vitro doxycycline MICs of >0.125 μg/mL to >4.0 μg/mL,[33, 37] however there is not a strict correlation between treatment failure and tested MIC so the clinical relevance of these findings are unclear. Several small population-level studies in communities with high background doxycycline use or subsequent to mass-treatment programs for trachoma did not find evidence of doxycycline resistance in CT.
Two studies have evaluated tetracycline resistance in TP. In China, molecular typing of serum from 438 case-patients  with syphilis found no evidence of a mutation in the 16S rRNA gene that is associated with tetracycline resistance in other bacterial species. A similar study of 53 case-patients in Italy  also did not identify any doxycycline resistance mutations. Complete genome sequencing of TP  has not found genetic elements associated with gene transfer mechanisms. That suggests that TP is less likely than other bacteria to develop plasmid-mediated antimicrobial resistance. However, macrolide resistance in TP has been documented to occur due to a single point mutation suggesting the potential for tetracycline resistance.
Antimicrobial resistance in Mycoplasma genitalium (MG), a frequent cause of non-gonococcal urethritis in men, is also a growing concern.[42, 43] Even though tetracyclines have low efficacy against MG, doxycycline is a recommended alternative regimen because of emerging resistance to first-line treatments. In a sub-study of the ANRS IPERGAY doxycycline extension, 11% of the 210 participants tested positive for MG at baseline and eleven participants acquired MG during the study.
Azithromycin and fluoroquinolone resistance was identified in 70% and 15% respectively of tested specimens. Broad doxycycline use in populations with high prevalence rates of MG could decrease treatment options for that bacteria. MG prevalence and antibiotic susceptibilities should be examined in future studies.
Finally, Doxy PEP/PrEP could contribute to development of doxycycline resistance in commensal organisms, including those with the potential to transmit resistance. Studies of military deployed overseas taking doxycycline for malaria prophylaxis have found conflicting data on the impact of doxycycline prophylaxis on antimicrobial resistance in oropharyngeal and intestinal commensal organisms.[44-46] Further study is needed. While it is possible to evaluate the impact of doxycycline on oral and rectal flora by examining the microbiome and resistome in these areas, there are no standard guidelines for interpreting findings.
4.2.4. Community acceptability and perceptions
Multiple surveys have demonstrated that doxycycline prophylaxis is acceptable to MSM. In an online survey of 2,095 Australian MSM, 53% indicated they would be likely to take doxycycline to prevent syphilis and 76% indicated they would take doxycycline to reduce syphilis in the community. Among 1,301 users of a U.S. social-networking app for MSM, 84% were interested in trying Doxy PEP. Interest was higher among African American and Latino/a respondents. At a joint Australia-New Zealand HIV/STI scientific meeting of clinical and public health experts in 2015, 52% of 63 providers felt that the benefits of doxycycline prophylaxis outweighed the risks, although 88% had concerns about antimicrobial resistance.
Some MSM in North America and Europe may already be using doxycycline for STI prophylaxis. In a survey of MSM taking HIV PrEP in the U.K. six of 106 respondents reported taking doxycycline to prevent STIs in the previous 6 months. In the ANRS IPERGAY Doxy PEP study  3-13% of participants in the placebo group had detectable doxycycline blood levels at each study visit. Doxycycline is also frequently available through online companies selling HIV PrEP.
Researchers and study participants have expressed concern about the potential for confusion between Doxy PEP/PrEP and HIV PrEP. Both medications can be used daily or intermittently. HIV-infected individuals may believe themselves ineligible for Doxy PEP/PrEP. HIV-uninfected individuals may not understand that HIV PrEP does not protect them against STIs and Doxy PEP/PrEP does not protect them from HIV. Effective educational campaigns, designed using evidence from ongoing and future studies, will be critical to address those concerns.
4.2.5. Risk compensation
Investigators have documented decreased condom use among MSM using HIV PrEP. While reports from completed Doxy PEP/PrEP trials have not identified similar changes in risk behavior,[16, 17] findings from the ongoing Canadian DuDHS study suggest some risk compensation might occur. Notably, risk compensation among people taking HIV PrEP was not identified in the initial placebo-controlled trials, but only became evident in later uncontrolled trials.
4.2.6. Risk/benefit and cost-effectiveness
While the benefits of HIV PREP as a way to prevent a life threatening infection are clear, the risk-balance of STI prevention may be more uncertain. As Golden and Handsfield suggest, a key issue to consider is which benefits of Doxy PEP/PrEP are most important to prioritize. While STI treatment has significant personal and financial costs, and STIs can cause serious sequelae in men (e.g., blindness and hearing loss due to syphilis), much of the direct STI morbidity is in women (infertility and adverse pregnancy outcomes). Primarily using Doxy PEP/PrEP in MSM, a population at high risk for bacterial STIs, might have relatively limited impact on reproductive health outcomes at the population level. The question of which benefits to focus on will also directly impact the cost-effectiveness of Doxy PEP/PrEP as the number of people who would need to receive treatment to avert a negative outcome will vary substantially depending on the outcome selected.