CROI 2023: Single dose doxycycline as PEP for STIs (DoxyPEP): five studies
10 March 2023. Related: Conference reports, Coinfections and complications, CROI 30 (Retrovirus) 2023.
Kirk Taylor, HIV i-Base
This report covers five oral presentations on using the antibiotic doxycycline (Doxy) – used to treat chlamydia, syphilis and susceptible gonorrhoea – as post-exposure prophylaxis (DoxyPEP) for STIs; but antibiotic resistance is a concern.
These studies were all included in a symposium at CROI 2023 on DoxyPEP and STI prevention. [1-5]
- A DoxyPEP PK study of vaginal and rectal tissues reported that a single 200 mg dose reaches levels >4x minimum inhibitory concentration (MIC) for chlamydia and syphilis for 2-4 days. However, levels of protection are lower for gonorrhoea and the 4x MIC threshold was not achieved in rectal tissue. 
- In a French study in gay men, DoxyPEP reduced the incidence rate of chlamydia and syphilis cases from 35.4 to 5.6/100 person-years. The same study also reported that the meningococcal vaccine (4CMenB) reduced the rates of gonorrhoea by 53%. 
- A US study reported that antibiotic resistance rose 8% for those on DoxyPEP but MRSA detection rates were unchanged. 
- A study of cisgender women in Kenya reported an overall decrease in the absolute number of bacterial STIs for those receiving DoxyPEP, however this was not statistically significant. 
- A retrospective study of DoxyPEP use in the US suggested that prescribing DoxyPEP for one year following an STI diagnosis may be more efficient than blanket prescribing of Doxy to all high-risk groups. 
PK parameters for DoxyPEP in mucosal tissues
Doxy was detected from swabs of mucosal tissues (anal and oropharyngeal) where STI exposure occurs and levels persist above the MIC. 
A PK study of anal and vaginal mucosal tissue was conducted to determine whether levels are sufficiently high to support DoxyPEP use by women.
Participants received a single dose of DoxyPEP (200 mg) and plasma, rectal and vaginal PKs were evaluated for 7 days. The time to Cmax increased for plasma (4hrs), vaginal (8hrs) and rectal (48hrs) samples.
Cmax levels in mucosal tissues peaked over 5x MIC for chlamydia and syphilis and remained >4x MIC for 48hrs. The MIC for gonorrhoea is higher and levels only reached 4x MIC for 11 hours in vaginal tissue and did not reach this level in rectal tissue.
Participants (n=20) were enrolled onto the study; 55% (n=11) were Black and 45% (n=9) were women, Median age was 38 for men and 34 for women.
Incidence of STIs using DoxyPEP or 4CMenB vaccine
The incidence rate of bacterial STIs for gay men on PrEP was reported as 75.8/100 person-years in the ANRS Previnir HIV PrEP study. DoxyPEP reduced chlamydia and syphilis by 70% but there was no significant impact on gonorrhoea in France where tetracycline resistance is very common (65% in 2021). 
Meningitis and gonorrhoea share outer membrane vesicle (OMV) proteins and the 4CMenB vaccine could potentially reduce gonorrhoea transmission by more than 50%.  An oral presentation at CROI2023 by Jean-Michel Molina from the University of Paris, reported the time to gonorrhoea infection after receiving the 4CMenB. 
Participants were randomised to receive 4CMenB vaccine (n=257) or not (n=245) and followed up for 96 weeks. Gonorrhoea transmission was lower for people who received the vaccine (17 vs 32 cases; adjusted hazard ratio (AHR): 0.49 (95%CI: 0.27 to 0.88). No drug related serious adverse events (AEs) were reported. These data further support development of vaccines to prevent gonorrhoea transmission.
DoxyPEP and incidence of chlamydia and syphilis evaluated within the same study.
The study randomised 502 gay and bisexual men (2:1) with recent history of STIs to receive DoxyPEP (n=332) or standard of care (SOC) (n=170). DoxyPEP needed to be taken within 72 hours of sex.
DoxyPEP reduced incidence of chlamydia and syphilis from 35.4 to 5.6 per 100 person years (AHR: 0.16, 95% CI 0.08 to 0.30).
Gonorrhoea cases were lower for people in the DoxyPEP arm with an AHR of 0.49 (95% CI: 0.32 to 0.76). Tet-R gonorrhoea was reported at baseline (n=7) on DoxyPEP (n=21) and SOC (n=37), however the proportion of highly resistant gonorrhoea was 14.4x greater in the DoxyPEP group.
Adherence to DoxyPEP was 80% and three people discontinued due to gastrointestinal AEs or fear of AEs.
Participants were white (80.5%), median age was 39 years (IQR: 33 to 47) and the median number of STIs in the previous year was 2 (IQR: 1 to 2) with gonorrhoea most frequently reported (68%).
This study originally planned to enrol more than 700 participants but was stopped early when results for both interventions were clearly seen to be effective.
Antibiotic resistance and DoxyPEP use was evaluated in an open label trial from the US in an oral presentation by Anne Luetkemeyer from UCSF, San Francisco. 
The study enrolled 637 gay and bisexual men and trans women who were either on ART or PrEP and who had had an STI in the preceding year.
Participants were randomised 2:1 to receive a single dose of DoxyPEP (200 mg) within 72 hours of condomless sex or standard of care (SOC; no doxy). The independent DSMB recommended early closure of the SOC arm after five months when all participants were given access to DoxyPEP.
Drug resistance was assessed at months 0 and 12 by culturing bacteria (S. aureus) from nasal/oropharyngeal swabs. Tet-R gonorrhoea incidence was similar for participants at baseline and those that received DoxyPEP. S. aureus colonisation decreased by 14% for the DoxyPEP group and Doxy-resistant S. Aureus levels increased 8%. MRSA levels were 6% for those on DoxyPEP and SOC and no changes were detected in Doxy-resistant MRSA. Two-thirds of commensal Neisseria species had Doxy resistance and was not affected by DoxyPEP use.
DoxyPEP in cisgender women in Kenya
In another oral presentation, Jenell Stewart from University of Minnesota reported the use of DoxyPEP in cisgender women in Kenya.
This study randomised 449 women on HIV PrEP to open-label DoxyPEP or SOC in Kenya. 
Median age was 24 years (IQR: 22 to 27) and baseline incidence of bacterial STIs was 18% for each group.
A total of 109 STIs were reported and included chlamydia (n=85) and gonorrhoea (n=31). Whilst the absolute number of cases in DoxyPEP were lower, the relative risk was 0.88 (95% CI: 0.60 to 1.29).
The study reported 80 pregnancies (44 for DoxyPEP and 36 for SOC). Adjusting for pregnancies increased the relative risk to 0.91 (95% CI: 0.62 to 1.35).
The reduction of STIs was not statistically significant and the researchers commented that this may be due to different levels of Doxy present in vaginal tissues.
No SAEs occurred but four participants reported social harms due to DoxyPEP. The number of Doxy-resistant gonorrhoea cases increased from 6 at baseline to 22 at follow-up.
Efficient prescribing of DoxyPEP
Antibiotic resistance is a global concern with long-term antibiotic use. A retrospective US cohort study evaluated DoxyPEP strategies to be able to reduce Doxy use, whilst maximising antimicrobial impact. 
This study evaluated electronic healthcare records (EHRs) from Fenway Health (Boston, MA). Data from 10,546 participants across 5 years were evaluated for Doxy prescriptions and outcomes giving 28,324 person-years of follow-up.
Ten potential DoxyPEP strategies were considered including prescribing DoxyPEP to specific groups (e.g. people with HIV and PrEP users) or one year’s prescription of doxyPEP following STI diagnosis. The investigators assumed that DoxyPEP would be prescribed to those matching the criteria and each person could access this multiple times.
The overall incidence rate for chlamydia, gonorrhoea and syphilis was 37/100 person-years. DoxyPEP was predicted to have similar efficacy for people living with HIV, PrEP users and non-PrEP users.
The authors predict that prescribing DoxyPEP for one year following an STI diagnosis could reduce subsequent STI cases by 42%. This strategy would be more efficient than prescribing DoxyPEP to all PrEP users.
The study included gay (87%) and bisexual (7%) men, transgender women (4%) and non-binary people assigned male sex at birth (2%). The cohort included people living with HIV (14%), PrEP users (54%) and non-PrEP users. Participants were Black (6.5%), Asian (5.9%) and Hispanic (14.6%).
Unless stated otherwise, references are to the Programme and Abstracts of the 30th Conference on Retroviruses and Opportunistic Infections, 19 – 22 February 2023, Seattle and hybrid. Some 2023 abstracts are available via the online CROI abstract database.
- Haaland R et al. Mucosal pharmacology of doxycycline for bacterial STI prevention in men and women. CROI 2023. Oral Abstract 118.
- Molina JM et al. ANRS 174 DOXYVAC an open-label randomized trial to prevent STIs in MSM on PrEP. CROI 2023. Oral Abstract 119.
- Luetkemeyer A et al. Doxy-PEP and antimicrobial resistance in S. Aureus, N. Gonnorhoea and commensal Neisseria. CROI 2023. Oral Abstract 120.
- Stewart J et al. Doxycycline postexposure prophylaxis for prevention of STIs among cisgender women. CROI 2023. Oral Abstract 121
- Traeger M et al. Potential impact and efficiency of Doxy-PEP among people with or at risk of HIV. CROI 2023. Oral Abstract 122
- Taylor K. Gonorrhoea vaccine may halve infections and combat drug resistance. HTB (01 July 2022).
This report was first published on 2 March 2023.