PrEP and PEP for sexually transmitted infections: what do we know about doxycycline as a strategy to prevent syphilis and chlamydia?

Prevention in Focus PiF 2020 Fall

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What is STI prophylaxis and why has it been getting attention lately?

Sexually transmitted infection (STI) prophylaxis refers to taking antibiotics to prevent getting bacterial STIs such as syphilis and chlamydia.1 The idea has been gaining attention lately, inspired by the success of HIV pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), which are used by HIV-negative people to help prevent HIV. In recent years, rates of bacterial STIs have been steeply rising in Canada and in many other countries,2,3 with a sharp increase in syphilis and gonorrhea infections among gay, bisexual and other men who have sex with men (gbMSM).2 This article will review the existing studies on the use of doxycycline for STI prophylaxis in gbMSM and transgender women who have sex with men who are at risk for contracting STIs.1 The article will also review the concerns that have been raised about potential consequences of STI prophylaxis use, such as drug side effects and antibiotic resistance.

What drug is being investigated for STI prophylaxis and why?

Although there is limited evidence as far back as the 1940s on the effectiveness of STI prophylaxis, there is renewed interest in the use of an antibiotic drug called doxycycline to prevent getting certain STIs.1,4 Doxycycline works by preventing certain bacteria, including some that cause STIs, from reproducing. This antibiotic and others from the same family have also long been used preventively by people at risk of being exposed to other infections such as malaria5 and Lyme disease.6 In addition, it is used to treat various skin conditions, including acne, often for long periods of time (i.e., months to over a year).7

In Canada, doxycycline is commonly used to treat syphilis and chlamydia,8 and researchers have suggested that it could similarly be used to prevent these infections. However, doxycycline is not a recommended treatment for gonorrhea, because up to 50% of gonorrhea infections are resistant to the drug.9 Therefore, it is expected that this drug will be less effective at preventing gonorrhea infections, although it may provide protection from strains of gonorrhea bacteria that are not resistant to doxycycline.

The doxycycline STI prophylaxis trials that have been done so far, or that are underway, have investigated two different approaches. The first involves taking doxycycline every day and is called STI pre-exposure prophylaxis (or STI PrEP).  With this approach, individuals who are at ongoing risk for STIs take 100 mg of doxycycline daily. The second approach is called STI post-exposure prophylaxis (or STI PEP). With STI PEP, individuals take the antibiotic after each potential exposure (e.g., after having sex without using a condom). With this approach, individuals take 200 mg of doxycycline within 72 hours after each potential exposure.

What do we know about how effective STI prophylaxis is?

Effectiveness on an individual level

Currently, there is not a lot of research on STI prophylaxis. The limited evidence does show some promise in terms of the ability of doxycycline prophylaxis to reduce certain STI infections; however, there is not yet enough evidence to conclude that this approach is effective. Three small randomized controlled trials have looked at how well it prevents STIs among HIV-positive men and transgender women who have sex with men and among HIV-negative men and transgender women who have sex with men who are taking HIV PrEP. Two of the studies used the STI PrEP approach, and the other used the STI PEP approach.  

A pilot study in Los Angeles looked at the feasibility of conducting a randomized controlled trial on the efficacy of STI PrEP. This study included 30 HIV-positive men and transgender women who have sex with men who had been diagnosed with syphilis two or more times since their HIV diagnosis.10 Study participants were randomly assigned to either an STI PrEP group that took daily doxycycline for 36 weeks or a contingency management group that did not receive STI PrEP but were given financial compensation if they tested negative for STIs at three different time points. The study continued for 12 weeks after the discontinuation of STI PrEP to find out whether any participants had subclinical syphilis infections (i.e., mild syphilis infections that did not show symptoms) that were not prevented and were not completely treated. Of the 30 people who started the study, 12 in the STI PrEP group and 11 in the contingency management group completed the study.  At 48 weeks follow-up, those in the STI PrEP group were significantly less likely to have been diagnosed with any STI (syphilis, chlamydia or gonorrhea) than those who did not take STI PrEP (six visits out of 53 visits resulted in an STI diagnosis versus 15 visits out of 49 visits, respectively). The authors state that it is unclear why this difference was found at 48 weeks, but it may be due to continued use of doxycycline by the PrEP group after the end of the study at 36 weeks.

An open-label randomized trial investigated the use of doxycycline as STI PEP.4 This study was a sub-study of the IPERGAY HIV PrEP trial, which looked at on-demand PrEP. This sub-study included 232 men and transgender women who reported having condomless sex with men. Half were randomly assigned to take STI PEP within 24 hours after sex (but up to 72 hours after) and the other half did not receive any STI prophylaxis. In total 73 participants presented with a new STI (syphilis, gonorrhea or chlamydia) during follow-up, 28 in the STI PEP group and 45 in the group that did not take STI PEP. This means that people taking STI PEP were 47% less likely to be diagnosed with an STI during follow-up than people not on STI PEP. In terms of the first instance of an STI diagnosis during follow-up, 28 people presented with chlamydia, seven in the STI PEP group and 21 in the group that did not take STI PEP. This means that people taking STI PEP were 70% less likely to be diagnosed with chlamydia. Similar results were found for syphilis, with 13 people presenting with syphilis, three in the STI PEP group and 10 in the group that did not take STI PEP. This means that people taking STI PEP were 73% less likely to be diagnosed with syphilis. There was no difference found with gonorrhea. In total 47 people presented with gonorrhea, 22 in the PEP group and 25 in the no-PEP group. Rates of serious adverse events and sexual practices were similar in the two study groups.

A recently completed pilot randomized controlled trial investigated the feasibility of combining daily HIV PrEP with daily STI PrEP in HIV-negative gbMSM and transgender women in Vancouver.11 The Dual Daily HIV and Syphilis Pre-Exposure Prophylaxis (DuDHS) study recruited 53 participants who had been diagnosed with syphilis at least once in the last three years.  All of the participants received HIV PrEP for 48 weeks.  Half were randomly assigned to take daily doxycycline as STI PrEP immediately and the other half were assigned to begin taking it after 24 weeks. Preliminary results from the first 24 weeks of follow-up showed that those not taking STI PrEP were significantly more likely to get an STI than those who were taking STI PrEP.  There were 21 STI diagnoses in total: four in those taking STI PrEP and 17 in those not taking STI PrEP. For syphilis, there was only one new infection, which occurred in someone not taking STI PrEP. For chlamydia, there were nine new infections, which all occurred in people not taking STI PrEP. Finally, for gonorrhea, there were 11 new infections, of which four occurred among those taking STI PrEP and four in those not taking STI PrEP.  The final participant completed their last study visit in May 2020, and data analyses are ongoing.

Several more studies about STI prophylaxis are underway, so more information about the effectiveness of STI prophylaxis will become available in the next few years.1

Potential to reduce community transmission

STI prophylaxis has the potential to help prevent STIs within the broader community of gbMSM, including among those who are not on STI prophylaxis. If a large enough proportion of gbMSM were to take it, the prevalence of certain STIs may decrease in the community. This would decrease the chance of coming into contact with someone who has an STI and result in fewer instances of transmission to others.

Given that STI prophylaxis has not been widely used, it is not possible to directly measure its impact on community transmission.  However, the impact can be estimated through modelling studies. One modelling study estimated a dramatic reduction in the number of syphilis infections on a community level in Victoria, Australia.12 The model predicted that if STI PrEP was 70% effective against syphilis and 50% of gbMSM used it, syphilis incidence would decrease by about 50% in one year and 85% after 10 years. Although these results are encouraging, they come from a model that was created using many assumptions based on the syphilis epidemic in Australia in 2011, and therefore the results may not be applicable to the current syphilis epidemic in Canada.   

Acceptability of STI prophylaxis

Several studies have found that gbMSM are interested in taking STI prophylaxis.1 A study of 424 gbMSM in Toronto and Vancouver looked at willingness to take PrEP or PEP to prevent syphilis and potentially chlamydia.13 Participants were told there was a risk of side effects, such as a mild upset stomach, or of antibiotic resistance that could make future infections harder to treat, and that it would involve going to a doctor every three months for blood work. Sixty percent of participants said that they would be willing to use syphilis PEP, and 44% said that they would be willing to use syphilis PrEP.

Another recent example is a survey of 1301 people in six cities in the United States who were recruited through a gay social networking app.  In that survey, 84% of the participants said that they were interested in trying STI PEP.14 Participants were told that STI PEP is an antibiotic that can prevent syphilis and chlamydia but they do not appear to have been told about potential side effects.

What are the side effects of doxycycline?

Doxycycline is generally well tolerated by people who take it to treat an STI.15 Many people do not experience side effects, and among those who do the most common side effects are gastrointestinal disturbances and skin issues such as developing a rash.

Although side effects are generally tolerable to people who take doxycycline for a short time to treat an STI, we don’t know as much about their tolerability with prolonged use. Side effects could deter some people from wanting to take the drug on an ongoing basis.

Limited data on side effects are available from the three randomized controlled trials that looked at the effectiveness of STI prophylaxis. Although the data available from these studies vary, roughly 25% of people who took STI prophylaxis reported some gastrointestinal issues while taking it.4,10,11 Although this led to some withdrawals from the studies, the majority of the people who experienced these side effects remained on STI prophylaxis. It should be noted that for the studies that included HIV PrEP in addition to STI prophylaxis it is impossible to determine if the side effects were the result of the HIV drugs or the antibiotic.

What is the concern about antibiotic resistance?

A major concern that has been raised about STI prophylaxis is the risk that increased antibiotic use could lead to antibiotic resistance.1,16 Antibiotic resistance occurs when bacteria mutate so that the antibiotics that are used to treat or prevent bacterial infections don’t work anymore. The more antibiotics people in a population take, the more likely it is that drug-resistant strains of bacteria will develop. Once a person has a resistant strain of a bacterium, that strain can then be passed to others. This is a major threat to public health, because many of the illnesses that are currently considered easily treatable with antibiotics could become life threatening if current treatments stop working.17

Although the risk is still unknown, there is a concern that if more people start taking doxycycline, antibiotic-resistant strains of chlamydia and syphilis could become more common.16 Drug-resistant gonorrhea is less of a concern because doxycycline is not used to treat gonorrhea in Canada.8 In addition to the risk that bacterial STIs could become resistant to the antibiotics used to treat them, there is a risk that other bacterial infections could mutate to become resistant to doxycycline.1 This could happen if a person taking doxycycline as STI prophylaxis is infected with another bacterium that doxycycline is used to treat.  There is a risk that those bacteria would develop resistance as well, which would complicate treatment. Research is underway to investigate the impact of doxycycline on antibiotic resistance.

More research is needed to understand the benefits and risks of STI prophylaxis

Both the potential benefits and the potential risks of STI prophylaxis could be significant. At this time there is not a consensus about STI prophylaxis in the scientific and medical community.  There are many questions that are unanswered, including whether the prevention benefits justify the risk of potential antibiotic resistance.  Other questions that need to be answered relate to the eligibility criteria for recommending STI prophylaxis and the best dosing schedule.

There is wide agreement that more research is needed before STI prophylaxis can be broadly rolled out. An international team of health experts from academic, clinical and community settings met in March 2019 to review the evidence.  They concluded that STI prophylaxis shows promise but much more research is needed before it can be used broadly.1  Public Health England has released a position statement saying that it does not endorse the use of STI prophylaxis outside of research studies.18

Although a parallel has been drawn between STI prophylaxis and HIV PrEP, it is important to understand that there are big differences between the two medications that would affect the risk-benefit calculation. HIV cannot be cured and requires lifelong treatment, whereas syphilis and chlamydia can be cured relatively easily. Also, it is very rare for a person to contract HIV if they are taking HIV PrEP consistently and correctly, whereas the risk reduction from STI prophylaxis appears to be much lower. On the basis of these two points, it can be argued that the benefits of HIV prophylaxis are much greater than the benefits of STI prophylaxis.

Should service providers promote the use of STI prophylaxis?

At this point in time, given that there are many unanswered questions about STI prophylaxis, it is not widely prescribed or formally recommended in any jurisdiction. If a client is interested in taking STI prophylaxis, they should be educated about the potential benefits as well as the potential risks. Clients who are at risk for STIs should be educated about ways to reduce their risk (such as using condoms when having sex) and about the importance of regular STI testing.

Related resources

8 Questions about PrEP for Guys (CATIE)

PrEP to Prevent HIV: Your Questions Answered (CATIE)

Is PrEP Right for Me? [Pocket card] (CATIE)

Sex Toy Stories: A user's guide to HIV and STI prevention (Canadian Public Health Association)

 

References

  1. Grant JS, Stafylis C, Celum C, et al. Doxycycline prophylaxis for bacterial sexually transmitted infections. Clinical Infectious Diseases. 2020;70(6):1247-53.
  2. Public Health Agency of Canada. Report on sexually transmitted infections in Canada, 2017. Ottawa: Public Health Agency of Canada; 2019 Nov. 25. Available from: from: https://www.canada.ca/content/dam/hc-sc/documents/services/publications/diseases-and-conditions/sexually-transmitted-infections-canada-2017-infographic/STI_2017_20191113_EN.PDF
  3. World Health Organization. Report on global sexually transmitted infection surveillance 2018. Geneva: World Health Organization; 2018. Available from: https://www.who.int/reproductivehealth/publications/stis-surveillance-2018/en/
  4. Molina JM, Charreau I, Chidiac C, et al. Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. The Lancet Infectious Diseases. 2018;18(3):308-17.
  5. Gaillard T, Madamet M, Pradines B. Tetracyclines in malaria. Malaria Journal. 2015;14(1):445.
  6. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. New England Journal of Medicine. 2001;345(2):79-84.
  7. Sloan B, Scheinfeld N. The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert Opinion on Drug Safety. 2008;7:571–7.
  8. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections. Ottawa: Public Health Agency of Canada, 2016. Available from: https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines.html
  9. Public Health Agency of Canada. Report on the enhanced surveillance of antimicrobial-resistant gonorrhea: results from 2014 and 2015. Ottawa: Centre for Communicable Diseases and Infection Control, Infectious Disease Prevention and Control Branch, Public Health Agency of Canada; 2018. Available from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/2014-2015-report-enhanced-surveillance-antimicrobial-resistant-gonorrhea.html
  10. Bolan RK, Beymer MR, Weiss RE, et al. Doxycycline prophylaxis to reduce incident syphilis among HIV-infected men who have sex with men who continue to engage in high risk sex: a randomized, controlled pilot study. Sexually Transmitted Diseases. 2015;42(2):98-103.
  11. Lawson-Tattersall TL, Mohammed S, Edward J, et al. Preliminary results of the Dual Daily HIV and Syphilis Pre-Exposure Prophylaxis (DuDHS) Trial. In : Abstracts of the 29th Annual Canadian Conference on HIV/AIDS Research, Quebec City, Quebec, May 1, 2020. Abstract KP4.01. Available from: https://www.youtube.com/watch?v=TbKbPlYT1xE&feature=youtu.be
  12. Wilson DP, Prestage GP, Gray RT, et al. Chemoprophylaxis is likely to be acceptable and could mitigate syphilis epidemics among populations of gay men. Sexually Transmitted Diseases. 2011;38(7):573-9.
  13. Fusca L, Hull M, Ross P, et al. High interest in syphilis pre-exposure and post-exposure prophylaxis among gay, bisexual and other men who have sex with men in Vancouver and Toronto. Sexually Transmitted Diseases. 2020;47(4):224-231.
  14. Spinelli MA, Scott HM, Vittinghoff E, et al. High interest in doxycycline for sexually transmitted infection postexposure prophylaxis in a multicity survey of men who have sex with men using a social networking application. Sexually Transmitted Diseases. 2019;46(4):e32-4.
  15. Peyriere H, Makinson A, Marchandin H, et al. Doxycycline in the management of sexually transmitted infections. Journal of Antimicrobial Chemotherapy. 2018;73:553-63.
  16. Siguier M, Molina JM. Doxycycline prophylaxis for bacterial sexually transmitted infections: promises and perils. ACS Infectious Diseases. 2018;4(5):660-3.
  17. World Health Organization. Antibiotic resistance.  Geneva: World Health Organization; 2018 Feb. 5. Available from: https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
  18. Public Health England. Position statement on doxycycline as post-exposure prophylaxis for sexually transmitted infections. London: Public Health England; 2017 Nov. Available from: https://www.bashhguidelines.org/media/1156/doxy_pep_statement_v5_phe_bashh.pdf

 

About the author(s)

Mallory Harrigan is CATIE's knowledge specialist, HIV testing. She has a Master’s degree in community psychology from Wilfrid Laurier University.