Pilot study suggests that PrEP for other STIs might work

Doxycycline cuts STI rate by 70% in at-risk gay men

Gus Cairns
Published: 12 February 2015

A small pilot study using a daily dose of the antibiotic doxycycline as pre-exposure prophylaxis (PrEP) against sexually transmitted infections (STIs) has found that a group of HIV-positive gay men taking doxycycline was more than 70% less likely to be infected with an STI than men given financial incentives to avoid STIs, a significant difference. There were 76% fewer cases of syphilis, although the small size of the study meant that this difference was not statistically significant.

The authors suggest that “the use of daily doxycycline against syphilis would.be an appropriate prevention tool…for a relatively small yet epidemiologically important population” of gay men. They add that the 77% overall retention rate in the pilot study “suggests that a clinical trial in a persistently high-risk group” of HIV-positive gay men “is feasible”.

The study - participants

The researchers recruited a group of 30 HIV-positive gay men/transgender women from the Los Angeles LGBT Center HIV Clinic who had had at least two documented and treated infections with syphilis since their HIV diagnosis. All but one were white of whom 60% were Hispanic, their median age was early 40s and their median duration of HIV infection was 8-12 years.

They were randomised into two groups of 15. One group was given 100mg doxycycline capsules to be taken once a day as PrEP against STIs. The other were given financial incentives to avoid STIs: while all participants were given $25 per study visit, control arm participants received an additional $50, $75 and $100 if they remained STI-free at weeks 12,14 and 36 of the study.

Doxycycline PrEP was given for 36 weeks and participants came back for one more visit at week 48 to see if there had been any STI infections in the three months after doxycycline PrEP stopped.

Eighty per cent of participants in the PrEP arm and 73% in the comparator arm completed the study. One person experienced side effects due to doxycycline that led him to stop taking it (heartburn, gastro-oesophageal reflux).

The study - adherence

Drug adherence was measured with drug-level monitoring in the PrEP arm. There is no existing therapeutic level established for doxycycline against syphilis, though the authors comment that as little as one dose per week has been found to prevent leptospirosis (Weil’s disease), caused by bacteria of the same type as syphilis. The authors selected a level of 1000ng/ml in blood as an indicator of daily adherence.

Overall, participants in the doxycycline arm had levels exceeding this on 24 out of 39 visits (62%). If people lost to follow-up were counted as having zero adherence, then this equated to 53% adherence in the entire study group. Adherence was somewhat lower on the third, week-36 visit (53%, or including people lost to follow up, 47%).

Sixty-two per cent of participants had levels indicative of daily dosing on two out of three study visits but only 31% on all three visits. However only two out of 13 participants with drug levels measured at weeks 24 and 36 had undetectable levels of doxycycline, indicating that 85% of participants had taken at least one dose of PrEP in the 4-5 days before their visit.

The study - infections

There were 21 new STI infections - nine syphilis and twelve gonorrhoea or chlamydia – in the 30 participants during the 11-month study.

There were 15 STI infections in the financial-compensation arm and six in the doxycycline arm. This translated into an odds ratio of 0.27 or a 73% reduction in the likelihood of STI infection, and was statistically significant (95% CI 0.09-0.83, p = 0.02). At week 36, when PrEP should have run out, there were twelve versus five STIs and this was not statistically significant: however, as the researchers comment, the drug levels indicate that some participants might have been taking doxycycline less than daily, so may have continued to take it beyond week 36, influencing the final outcome.

There were seven syphilis infections in the financial-compensation arm and two in the doxycycline arm, but this 76% reduction was not statistically significant. Nor were the eight versus four chlamydia or gonorrhoea infections (64% reduction).

No one taking doxycycline had more than one STI diagnosis during the study, whereas in the comparison arm two participants had three STIs diagnosed and two had two diagnosed – two of them with successive syphilis infections.

Interestingly, both of the two syphilis infections, and one of the gonorrhoea infections in the PrEP arm were in participants with drug levels indicating daily PrEP adherence – though the infection could have happened at any time in the twelve weeks preceding the clinic visit at which a sample was taken for drug level monitoring.

There were no differences in sexual behaviour between the PrEP and the financial-compensation participants. Sixty-six per cent in the PrEP arm and 62% in the other harm reported sex without a condom in the previous three months, with episodes of sex roughly equal between regular and casual partners. About 20% reported using methamphetamine.

Implications and conclusions

If this pilot study leads to interest in developing PrEP for STIs further, one of the biggest concerns will be antibiotic resistance. Antibiotic-resistant gonorrhoea is a major concern, although the adoption of stricter prescribing guidelines appears to have led to falls in drug resistance in the US and UK.

The authors comment that doxycycline has not been used against gonorrhoea and there is little evidence of doxycycline resistance in chlamydia. However although the syphilis bacterium does not easily develop resistance, it has done against some of the drugs used to treat it in patients allergic to penicillin, the first-choice treatment, including doxycycline and other antibiotics of its class. Although PrEP is less likely to cause resistance than suboptimal adherence to treatment of an existing infection, syphilis resistance is clearly to be avoided.

The authors comment that this implies that “daily doxycycline prophylaxis against syphilis would not be an appropriate prevention tool for most HIV-[positive gay men] but only for a relatively small, yet epidemiologically important population, where its use may outweigh the theoretical resistance risks.”

They point out that syphilis is a well-known “amplifier” of HIV infection: HIV-negative people with it are 2-9 times more likely to acquire HIV, and syphilis approximately doubles the viral load in an HIV-positive person not taking HIV therapy. STI PreP could therefore help reduce HIV transmission considerably, as well as improving sexual health in a subset of gay men in its own right.


Bolan RK 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 42(2):98-103. 2015.

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