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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

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Summary

Background

Increased rates of sexually transmitted infections (STIs) have been reported among men who have sex with men. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of STIs.

Methods

All participants attending their scheduled visit in the open-label extension of the ANRS IPERGAY trial in France (men aged 18 years or older having condomless sex with men and using pre-exposure prophylaxis for HIV with tenofovir disoproxil fumarate plus emtricitabine) were eligible for inclusion in this open-label randomised study. Participants were randomly assigned (1:1) at a central site to take a single oral dose of 200 mg doxycycline PEP within 24 h after sex or no prophylaxis. The primary endpoint was the occurrence of a first STI (gonorrhoea, chlamydia, or syphilis) during the 10-month follow-up. The cumulative probability of occurrence of the primary endpoint was estimated in each group with the Kaplan-Meier method and compared with the log-rank test. The primary efficacy analysis was done on the intention-to-treat population, comprising all randomised participants. All participants received risk-reduction counselling and condoms, and were tested regularly for HIV. This trial is registered with ClinicalTrials.gov number, NCT01473472.

Findings

Between July 20, 2015, and Jan 21, 2016, we randomly assigned 232 participants (n=116 in the doxycycline PEP group and n=116 in the no-PEP group) who were followed up for a median of 8·7 months (IQR 7·8–9·7). Participants in the PEP group used a median of 680 mg doxycycline per month (IQR 280–1450). 73 participants presented with a new STI during follow-up, 28 in the PEP group (9-month probability 22%, 95% CI 15–32) and 45 in the no-PEP group (42%, 33–53; log-rank test p=0·007). The occurrence of a first STI in participants taking PEP was lower than in those not taking PEP (hazard ratio [HR] 0·53; 95% CI 0·33–0·85; p=0·008). Similar results were observed for the occurrence of a first episode of chlamydia (HR 0·30; 95% CI 0·13–0·70; p=0·006) and of syphilis (0·27; 0·07–0·98; p=0·047); for a first episode of gonorrhoea the results did not differ significantly (HR 0·83; 0·47–1·47; p=0·52). No HIV seroconversion was observed, and 72 (71%) of all 102 STIs were asymptomatic. Rates of serious adverse events were similar in the two study groups. Gastrointestinal adverse events were reported in 62 (53%) participants in the PEP group and 47 (41%) in the no-PEP group (p=0·05).

Interpretation

Doxycycline PEP reduced the occurrence of a first episode of bacterial STI in high-risk men who have sex with men.

Funding

France Recherche Nord & Sud Sida-HIV Hépatites (ANRS) and Bill & Melinda Gates Foundation.

Introduction

The global burden of sexually transmitted infections (STIs) worldwide is huge, with more than one million STIs acquired every day.1 Increased rates of STIs have been reported in several countries, in particular among men who have sex with men (MSM).2 In the USA, 2015 was the second year in a row with an increased incidence of all three bacterial STIs (gonorrhoea, Chlamydia trachomatis, and syphilis), with syphilis increasing at an alarming rate among MSM.3 High rates of STIs have also been reported in trials of pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine among high-risk MSM and during PrEP rollout, probably because of low condom use and frequent STI testing.4, 5, 6, 7, 8, 9 Although increased STI rates were reported before PrEP was implemented, STIs represent a growing concern among PrEP users and a major public health challenge.10 Because of the absence of effective vaccines against bacterial STIs, consistent condom use remains the cornerstone of prevention but biomedical interventions such as antibiotic prophylaxis might need to be revisited. The effectiveness of antibiotic prophylaxis for STIs has been assessed since the 1940s, with limited success so far because of the short-term benefit of antibiotics and the selection and dissemination of antibiotic resistance, in particular for gonorrhoea.11, 12, 13, 14, 15, 16 However, antibiotic resistance to Chlamydia trachomatis and Treponema pallidum remains rare, with no known resistance to doxycycline.17, 18 PrEP programmes that allow long-term follow-up and monitoring of high-risk individuals provide a unique opportunity to do research on STIs and assess new preventive strategies. Doxycycline has been used successfully for post-exposure prophylaxis (PEP) of Lyme disease and leptospirosis, two spirochaetal diseases, and its role in prevention of STIs has been investigated in a small trial of HIV-infected MSM.19, 20, 21 We therefore aimed to assess, in the open-label phase of the France Recherche Nord & Sud Sida-HIV Hépatites (ANRS) IPERGAY trial, whether PEP with doxycycline could reduce the incidence of bacterial STIs among high-risk MSM.

Research in context

Evidence before this study

Antibiotic prophylaxis has been used for decades as a biomedical intervention to contain the spread of sexually transmitted infections (STIs) in high-risk individuals. Early studies in the 1940s were done in the navy to assess the benefit of post-exposure prophylaxis (PEP) with sulfonamides or penicillin for gonorrhoea, but this approach was associated with rapid selection of antibiotic resistance. Similar results were observed in the 1980s with minocycline PEP for gonorrhoea, showing limited effectiveness in men exposed to gonococci resistant to minocycline. This strategy was subsequently abandoned. More recently, antibiotic prophylaxis for STIs has been assessed as a way to reduce the risk of HIV acquisition in female sex workers in developing countries by use of monthly periodic presumptive treatment with azithromycin. This strategy was associated with a modest reduction in the incidence of gonorrhoea and chlamydia but not of syphilis or HIV. Following the implementation of pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV acquisition in men who have sex with men (MSM), high rates of STIs have been reported in this population. We searched PubMed for articles published until Sept 8, 2017, using the terms “antibiotic”, “prophylaxis”, “men”, and “trial”, along with “STIs”, “gonorrhoea”, “syphilis”, or “chlamydia”. We reviewed 60 publications and identified two studies, one reported by the US military in 1979 on the use of minocycline PEP to prevent gonorrhoea but with no data for chlamydia or syphilis and another randomised trial of 30 HIV-infected patients involving daily doxycycline prophylaxis or incentive payments, which showed decreased incidence of STIs with antibiotic prophylaxis.

Added value of this study

This study is, to our knowledge, the first large, open-label, randomised trial assessing the efficacy and safety of a novel antibiotic PEP strategy for STIs involving doxycycline (200 mg taken within 24 h after sex) in MSM taking PrEP for HIV prevention. This study showed a high rate of STIs without prophylaxis, the majority of which were asymptomatic, but this antibiotic strategy showed significant benefit, with an overall 47% relative reduction in the incidence of a new STI. Although no clear benefit was shown for gonorrhoea, probably because of the already high rate of doxycycline resistance, a significant relative reduction in the incidence of chlamydia and syphilis was observed. The median use of doxycycline was 680 mg per month, with a good safety profile apart from an increased rate of gastrointestinal adverse events compared with PrEP alone.

Implications of all the available evidence

The results of this doxycycline PEP study for STIs in high-risk MSM taking PrEP show that this strategy can reduce the incidence of chlamydia and syphilis in this population with a good safety profile. Additional studies are needed to assess the full effect of this strategy on the selection of antibiotic resistance for gonorrhoea, syphilis, and chlamydia. Selection of tetracycline resistance remains an important potential risk of doxycycline PEP; we could not assess this risk because of the sample size and the relatively short period of follow-up. Pending additional studies, the use of doxycycline as PEP should be restricted to research purposes. In the future, this strategy might become an effective addition to a combined intervention approach to reduce the high rate of STIs in PrEP users.

Section snippets

Study design and participants

This open-label randomised trial was a substudy of the ANRS IPERGAY trial, which showed the efficacy of on-demand PrEP with tenofovir disoproxil fumarate plus emtricitabine in reducing HIV incidence among high-risk MSM.6 Following this result, an open-label study extension was implemented from Nov 4, 2014, to June 30, 2016, to provide all participants with tenofovir disoproxil fumarate plus emtricitabine until PrEP approval.22 In July, 2015, the ANRS IPERGAY protocol was again amended to

Results

From July 20, 2015, to Jan 21, 2016, 299 participants were screened. 232 participants were randomly assigned, 116 to the doxycycline PEP group and 116 to the no-PEP group (figure 1; table 1). Baseline characteristics of study participants are shown in table 2 and were well balanced across the two study groups. 22 participants (19%) in the doxycycline PEP group and 16 (14%) in the no-PEP group were diagnosed with a bacterial STI that was asymptomatic at the time of randomisation. One patient in

Discussion

The results of this open-label randomised trial show that, among high-risk MSM using PrEP with tenofovir disoproxil fumarate plus emtricitabine for HIV prevention, the use of doxycycline PEP following condomless sexual activity was associated with a significant decrease in the occurrence of a new bacterial STI, with an overall 47% relative reduction in the risk of acquiring a new bacterial STI (gonorrhoea, chlamydia, or syphilis). However, the short duration of follow-up in our study might have

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  • Cited by (0)

    Members of the ANRS IPERGAY Study Group are listed in the appendix

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