In the pre-acquired immune deficiency syndrome era, syphilis was an endemic infection in many populations of men who have sex with men (MSM) around the industrialized world.1–4 As sexual norms changed, in response to the human immunodeficiency virus (HIV) epidemic, syphilis essentially disappeared in many of these populations for a decade and a half, but then returned with sharp increases in incidence over the last decade.5–13 Although syphilis is easily curable, this resurgence in infection rates is of major public health concern. One of the concerns is that along with other anogenital infections, syphilis may increase the risk of HIV transmission.14–17 Indeed, syphilis epidemics have coincided with an increase in HIV diagnoses among MSM worldwide during the last decade.18–20 Epidemiologic data indicate that the incidence of syphilis is particularly high among MSM with HIV infection, with rates 5- to 10-fold higher than in MSM without HIV.21,22 Reasons for this differential are probably behavioral, reflecting serosorting for partners of the same serostatus among HIV-positive gay men or higher levels of risky sexual activity among these men,23–25 or the differential may be biologic and mediated by some form of immunologic susceptibility due to HIV infection.14,15,17
Since syphilis reappeared so strikingly in MSM populations, there have been considerable efforts directed toward control strategies, including increased partner notification and expanded syphilis screening.26–28 The main approach has been to increase testing and treatment rates, but it appears to be difficult to attain, let alone sustain, the intensity required to markedly reduce transmission.26,29,30 Campaigns have also focused on increasing condom use, but have had limited success as much transmission is among seroconcordant men who already have HIV infection and are not using condoms consistently.21,22 In its highly infectious early stage, syphilis transmission can also readily occur as a result of oral sex, which rarely involves the use of a condom.31
In this context, innovative approaches for controlling syphilis are urgently needed. One option could be the use of systemic medium-term chemoprophylaxis, using an antibiotic agent that is known to be therapeutically effective against syphilis (an approach we coin as “syphilaxis”). Such an approach could potentially provide protection for the individual as well as offer a public health strategy. To assess the feasibility of this approach, and in preparation for a large scale efficacy trial, we undertook mixed-method approaches involving social research and mathematical modeling to determine whether syphilis chemoprophylaxis is likely to be acceptable to gay men and, if it was made available, whether it would likely be effective in changing the course of syphilis epidemics.
We used distinct but complementary methods of data collection and analysis. Ethics approval was obtained from the University of New South Wales.
Acceptability Study Component
An online survey was conducted to estimate relative attitudes to specified interventions to reduce syphilis infections, in a large community-based sample. This was supplemented by focus group discussions to explore the reasons why or why not individuals would act on these intentions. Participants were recruited through a broad range of methods, including respondent-driven sampling and convenience sampling through established networks, both online and offline; on-site recruitment at gay community venues and events; and advertising through gay community websites.
Questions were asked initially about gay men's likelihood to adopt specific interventions in order to protect themselves from syphilis infection, and then again about reducing rates of infection within the gay community. Other questions covered sexual behavior in the preceding 6 months and extent of social engagement with other gay men. Free-text comments were also collected in the online survey.
Men were eligible for the study if they were homosexually identified or had had sex with another man in the previous year, and if they lived in Australia. Sexual identity was by self-definition. Of 4125 surveys started, 2095 provided sufficiently complete information to be included in these analyses (based on reporting of their HIV testing history and HIV serostatus, and at least some information about their sexual behavior). The mean age of respondents was 35.13 years (range, 15–87 years), 80.5% identified as gay, 53.6% reported completing some university education, and 83.9% were in paid employment. Most (84.8%) men had been tested for HIV, with 9.4% having tested HIV-positive and 75.4% testing HIV-negative. Among men who were not tested as HIV-positive, 58.8% indicated they had been tested in the previous year. More than half (55.9%) reported having a primary regular partner or boyfriend in the previous 6 months. More than ⅔ of those with a primary partner (70.7%) did not always use condoms with their regular partner during the previous 6 months. Among men who reported having sex with casual partners in the preceding 6 months, well over a third (38.1%) indicated that they had engaged in unprotected anal intercourse with a casual partner in the preceding 6 months. However, we were unable to ascertain the number of cases engaging in unprotected anal intercourse with partners of discordant or unknown HIV or syphilis status.
From the survey respondents, 787 men volunteered for further participation in the study and from these we recruited 23 volunteers for 5 focus groups—3 in Sydney and 2 in Melbourne. They were all mixed groups of HIV-negative and positive men except 1 group for HIV-positive men in Sydney.
The survey questions formed the basis of the focus group discussions. In these groups, we asked men to discuss their knowledge of syphilis and what they would be prepared to do to avoid it, including the possible use of chemoprophylaxis; and the feasibility of chemoprophylaxis interventions and how they could best be implemented. Men were informed of the proposed specific antibiotic, and there was extensive discussion about potential side-effects. They were asked about several periods of time of use and the respective acceptability for each.
Quantitative data were analyzed with Statistical Package for Social Sciences software (SPSS Inc., Chicago, IL). Descriptive statistics were used to compare men in 2 high-risk categories (men with more than 10 sexual partners in the preceding 6 months, and men who engaged in unprotected anal intercourse with casual partners in the preceding 6 months) with men who did not engage in these high-risk behaviors.
Qualitative data were analyzed by close reading of the transcripts by investigators who compared findings. This ensured that the dominant themes in the transcripts were identified and coded as they emerged from the data through the technique of constant comparison.32 Excerpts from the focus groups were used to demonstrate the attitudes of participants in their own words.
We extended a previously published33 individual-based mathematical model that simulates a population of sexually active gay men, tracks the formation and breakup of sexual partnerships, and records the transmission of syphilis and HIV. The model simulates a dynamic sexual partnership network that is updated according to daily probabilistic rates (as defined in the Appendix, Supplemental digital content 1, online only, available at: https://links.lww.com/OLQ/A15). In this model, gay men can participate in casual partnerships, form long-term partnerships, and/or engage in group sex. The number of sexual partnerships, and number and type of acts within partnerships is sampled for each man from empirically based distributions (mentioned in Appendix, Supplemental digital content 1, online only, available at: https://links.lww.com/OLQ/A15). The model also simulates syphilis (and HIV)-infected individuals as they progress in their infection with different levels of infectiousness. We also incorporate realistic syphilis testing rates depending on each man's sexual activity and HIV status. The model was implemented using Matlab and was specifically calibrated to match the estimated infectious syphilis diagnoses among gay men in Victoria, the Australian state that has reported the largest relative increase in syphilis. Univariate sensitivity analyses were carried out in the calibration process by varying parameters within plausible limits. The stochasticity involved in the probabilistic rates of random events simulated in the model was found to create more variability in model output than changes in parameter values. All model inputs and assumptions, along with detailed explanations and references to justify them, are presented in the Appendix (Supplemental digital content 1, online only, available at: https://links.lww.com/OLQ/A15).
We explored the potential impact of introducing syphilis chemoprophylaxis as an intervention. The overall effectiveness of chemoprophylaxis interventions depends on (i) coverage among the population; (ii) usage (adherence); and (iii) efficacy of the drug in protecting against syphilis. It is expected that the efficacy of a dose of doxycycline (100 mg once a day) will be close to 100% if there is high adherence. We conservatively assumed that chemoprophylaxis will have a use-effectiveness of 70% once imperfect adherence is taken into account. Use-effectiveness is defined as the actual effectiveness of doxycycline in reducing transmission risk, once levels of actual adherence are taken into consideration, in real-world conditions, and not effectiveness if there is 100% adherence. We also carried out sensitivity analyses, assuming use-effectiveness levels of 50% and 90%. This assumed level of efficacy is based on trial studies that have shown doxycycline has high prophylactic efficacy against leptospirosis (efficacy, 95%)34 and Lyme disease (efficacy, 87%).35 Adherence could be expected to be around 80% based on an estimate of 79% ± 14% from a meta-analysis of mean dose-taking compliance of any drug at 1 dose per day.36 Furthermore, we also extended our sensitivity analysis to include low levels of use-effectiveness, over the range of 0% to 90%.
Our model was used to project an expected syphilis epidemic trajectory over the next 10 years, under conditions that all parameters and screening rates remain unchanged and that there is no intervention with chemoprophylaxis. We then used our model to forecast the expected epidemiologic impact of introducing chemoprophylaxis that covers 50% of gay men who have greater than (i) 50 partners per 6 months (∼7% of the population); (ii) 20 partners per 6 months (∼37% of the population); (iii) 10 partners per 6 months (∼53% of the population); or (intravenously) 50% of all men. These simulations considered interventions of chemoprophylaxis that were implemented over 12 months duration or indefinitely. The median trajectory of 50 model simulations is shown in our results.
Acceptability of Chemoprophylaxis Against Syphilis
In the online survey, when asked whether they would be prepared to take pills every day for a period of time in order to reduce their own chances of a syphilis infection, 1104/2095 (52.7%; 95% confidence interval [CI], 50.6%–54.8%) of respondents indicated that they would be likely to do so, including 26.3% (95% CI, 24.4%–28.2%) who said they would be “very likely” to do so (Fig. 1A). However, when asked if they would be willing to do so if it would help reduce infections in the gay community as a whole, 75.8% (95% CI, 74.0%–77.6%) said they would be likely to do so, including 48.6% (95% CI, 46.5%–50.7%) indicating they would be very likely (Fig. 1B). When stratified by HIV status, HIV-positive men were slightly more likely than nonpositive men to indicate being very likely to take pills every day to protect themselves from infection (33.2% vs. 25.2%, P = 0.022), but there was no difference in their likelihood to do so to reduce infections in the community. When the analysis was restricted to men at higher risk, these proportions were similar to those for the entire sample (results not shown).
Men in the focus group discussions tended to be very enthusiastic about the idea of an antibiotic being made available to at-risk men to use prophylactically to reduce syphilis infections:
Sexually active and sexually adventurous men could, could choose to take the pill, trying to bring the rates down, I think that you, you might get the community responding in a big way to that (Focus Group 3, Melbourne)
For some men with HIV infection, the benefits of avoiding syphilis meant a small, easily manageable modification to their existing regimen of daily medication:
Personally, I'm taking a number of pills a day. One more pill which would help me not have to stress over that fact, I would find that beneficial. (Focus Group 2, Sydney)
However, other HIV-positive men did not wish to add to their intake of daily medication due to concerns about drug interactions. Some HIV-negative men expressed caution about taking medication for a condition that is yet to affect them:
I would not take it. I would not do it. I would have to get sick first. I would have to know I've got something before I started taking medicine. I would not take a preventative thing until I needed it. (Focus Group 4, Melbourne)
The duration and adherence to chemoprophylaxis were other concerns that were expressed:
Participant 1: A week's a push.
Participant 2: Definitely. A week. You start talking “weeks” and they'd say, “Oops, missed a day.” I think everyone knows that they're going to do that. (Focus Group 1, Sydney)
As such, long-term chemoprophylaxis was considered to be less attractive, but men did suggest targeting campaigns to coincide with major gay community events. This would provide both, an opportunity to take advantage of their associated publicity, and protection when the community was most at risk.
Accessibility and cost were seen as barriers to uptake—men would prefer not to have to visit their doctor or pay for a prescription to obtain the medication:
Participant 1: Put a basket of them on every [gay] bar... Yeah, I'm like, that's what we do now. Condoms are there.
Participant 2: Is it prescription though now?
Facilitator: At this stage, yeah.
Participant 1: So you'd have to see a doctor?
Participant 3: It's a big call. (Focus Group 1, Sydney)
I don't think [anyone will pay] because everyone doesn't believe they'd get syphilis. So if that's the case ... I mean I don't think I should have to pay for it. You know, that's the attitude. (Focus Group 2, Sydney)
Mathematical Modeling of the Effectiveness of Chemoprophylaxis
We found that chemoprophylaxis used by subpopulations of highly sexually active gay men can have a substantial epidemiologic impact and change the course of syphilis trends, under a variety of use-effectiveness assumptions (Fig. 2). For example, chemoprophylaxis with 70% use-effectiveness used consistently by 50% of gay men is expected to reduce the number of incident cases of syphilis by 49% over 12 months in the absence of other interventions (Fig. 2B). Even moderate (50%) use-effective chemoprophylaxis used for 1 year could have a noticeable impact on syphilis epidemics (Fig. 2A). Although short-term chemoprophylactic interventions can avert substantial numbers of infections and reduce syphilis prevalence in the population, it could be expected that if other interventions are not implemented and behavior remains unchanged, syphilis incidence would increase once chemoprophylaxis interventions are ceased (Fig. 2).
We also used our mathematical model to investigate the potential impact of long-term (“ongoing”) use of syphilis chemoprophylaxis whereby drugs could be used by some men on a frequent basis for several years. In Figure 3, we present expected epidemic trends in the context of ongoing use of syphilis chemoprophylaxis. We show that even in the absence of any other interventions or change in behavior, moderate coverage of chemoprophylaxis can reverse syphilis epidemics. After 5 years of 70% use-effective chemoprophylaxis used by 50% of gay men, the annual number of syphilis diagnoses could be expected to be reduced by 77% (Fig. 3B), and 90% use-effective chemoprophylaxis could reduce the number of annual syphilis diagnoses by 86% (Fig. 3C); 10 years of use would reduce the number of diagnoses by 85% and 92%, respectively. Prevalence trends would follow a pattern similar to the expected trends in diagnoses (results not shown).
There is uncertainty in the actual use-effectiveness that will be achieved among populations of gay men. If it was made widely available, use-effectiveness could be a product of the coverage (which subpopulation and what percentage of this subpopulation uses the drug at any time), frequency of use among individuals in the covered subpopulation, and actual efficacy of the drug for people who use it. Therefore, we investigated the expected relationship between the percentage of infections averted and the use-effectiveness of chemoprophylaxis (Fig. 4). We find that even at low use-effectiveness levels, there is the potential for significant preventative benefit; for example, 10% use-effectiveness results in an expected ∼20% prevention in the number of new infections (Fig. 4). The relative benefit saturates for high use-effectiveness levels (Fig. 4).
We also explored the potential impact of syphilis chemoprophylaxis that targeted men, based on their level of sexual activity. Not surprisingly, the greatest efficiency (in terms of the ratio of total infections averted per person prophylaxed) will be achieved when targeting men with the greatest rate of sexual partner acquisition. Although men who have more than 50 partners per 6 months make up just 7% of the Australian gay population, targeting this group alone can result in an estimated 29%, 39%, and 51% of the reduction that would be achieved if chemoprophylaxis was provided to all gay men for 50%, 70%, and 90% use-effectiveness, respectively (Fig. 3). However, our model suggests that there is a certain coverage level beyond which the additional epidemiologic impact is very modest. Almost the same reduction in incidence can be achieved by targeting men who have greater than 10 partners per 6 months (53% of the population), compared with providing syphilis chemoprophylaxis to all gay men (Fig. 3).
Since HIV-infected men are disproportionately affected by syphilis, we used our model to explore the expected effect of targeting chemoprophylaxis to HIV-infected men. We found that targeting these men will be an efficient way of using chemoprophylaxis. Although HIV-infected men represent a relatively small proportion of all gay men, targeting chemoprophylaxis at these men will likely have a moderately large impact on the epidemic in the entire gay population. Specifically, targeting 50% of HIV-infected men (i.e., approximately just 5% of the gay population) with 70% use-effective chemoprophylaxis for 1 year was modeled to lead to an ∼25% reduction in incident infections in the population.
Traditional public health responses have so far been unsuccessful in controlling resurgent epidemics of syphilis among gay men.29,30 Innovative interventions that are acceptable and more effective are needed. This is the first research program which has combined social research and mathematical modeling to explore the potential acceptability and efficacy of syphilis chemoprophylaxis in gay men. The social research suggested general acceptability among gay men and the modeling showing that a public health intervention of syphilis chemoprophylaxis can potentially reverse the increasing epidemic trends.
The social research findings show that syphilaxis is likely to be acceptable to gay men as a community level strategy, but less attractive as an individual protective strategy. This suggests that appeals to altruism for the benefit of the community, in order to reduce infection risk for everyone, will be more successful than approaches that target individuals to protect themselves from infection. This result is consistent with findings from previous social research studies among gay men.37–39 Notably, this survey was conducted before any wide-spread community debate or educational programs about syphilis or addressing the concept of chemoprophylaxis against syphilis. It would be valuable to know whether the survey respondents are similar to men who chose not to participate in the survey. As with any online convenience sample, it is not possible to know how many men received an invitation to participate. However, men who only partially completed the survey were slightly younger (mean age, 34.1 vs. 35.1; P = 0.035), and were somewhat less likely to have university-level education (48.8% vs. 54.0%, P = 0.015) compared to men who fully completed the survey. However, otherwise, the 2 groups were very similar: they lived in similar geographic locations, they were as likely to identify as gay, and had similar levels of involvement in gay community life. There also appeared to be little difference in their likelihood to engage in a range of sex practices, including unprotected anal intercourse with casual partners. Therefore, it may not be inappropriate to take these survey results as representative of the population of gay men, but caution should still be taken as we have no information about men who did not initiate the survey. Given that the men who completed the survey were slightly older and slightly more sexually active (i.e., more likely to report any recent sexual partners), both of which fit with the epidemiology of syphilis among gay men, it is probably reasonable to presume that the survey results could be relevant to those at highest risk.
We provided estimations of the potential epidemiologic impact of syphilis chemoprophylaxis and found that it has the potential to prevent up to ∼85% of new infections over 10 years (Fig. 3) and could be targeted to more highly sexually active men and achieve a similar impact to reaching all gay men. Moreover, control of syphilis during shorter-term chemoprophylaxis interventions could afford the opportunity to increase syphilis awareness and scale-up other campaigns that address syphilis testing rates, partner notification, behavior change, and other interventions. If chemoprophylaxis is widely used by gay men during a time-limited and focused intervention and becomes more acceptable within the gay community, it may become an option for gay men in protecting their health in the longer term. However, the feasibility of wide-scale use of chemoprophylaxis may be a major challenge to this strategy. Even 50% of gay men in an entire population are unlikely to be persuaded to regularly take a drug to protect themselves or the community from syphilis. But if smaller subpopulations are targeted then it is also possible to have a substantial broader population benefit, particularly if men at highest risk use the drugs (Figs. 2, 3). Targeted interventions at appropriate times should also be considered if chemoprophylaxis is to be implemented as a public health strategy since it is unlikely that men would be willing to take chemoprophylaxis for a year or more at a time. If chemoprophlaxis is only used for short durations and scaled up at specific times, it is analogous to mass treatment strategies, except that it is for men presumed to be uninfected.
A mass treatment intervention of syphilis among heterosexuals was conducted in British Columbia approximately 10 years ago.40 In that setting, there was a rebound in syphilis cases and the absence of a sustained effect suggesting that targeted mass treatment for syphilis, even though feasible, should not be done routinely. Similarly, our modeling demonstrated that if an intervention using chemoprophylaxis was to stop or slow down, such as after a 12 month intensive intervention, then there would be a rebound in syphilis cases. Therefore, if syphilaxis was to be used in an intervention, epidemic trends should be carefully monitored and be used to inform the frequency and coverage of public health programs and how to complement chemoprophylaxis with other interventions over the longer term.
Although we have shown that syphilaxis is likely to be both acceptable and effective, there are a number of implementation and public health issues that would need to be addressed before there is widespread uptake. First, efficacy of the chemoprophylactic drug needs to be demonstrated in a randomized controlled trial setting. Second, options for easy access to chemoprophylactic drugs need to be investigated. Populations of people at risk are only likely to adopt chemoprophylaxis if the drugs can be accessed in a convenient manner. Third, potential adverse events, such as drug resistance, associated with high levels of chemoprophylactic drug use in communities need to be identified and managed. Resistant strains of Treponema pallidum are not known to emerge in the presence of doxycycline. However, it would be important to closely monitor the effects of regular use of the drug for the potential emergence of resistant strains of various bacteria and not just sensitivity of T. pallidum. Fourth, cost-effectiveness analyses should be conducted to ensure that chemoprophylaxis-based interventions are financially viable. Finally, if adoption of chemoprophylaxis leads to condom replacement then it is possible that the intervention could actually lead to increased risk of acquiring syphilis, HIV, and other sexually transmissible infections. While such behavioral disinhibition is possibile, there is no empirical evidence that it will occur in the context of chemoprophylaxis. A recent study of preexposure antibiotic prophylaxis for syphilis in African Americans actually found that this intervention was associated with a decrease in sexual risk behavior.41 However, research in other contexts is required. It is also important that there is good community education to ensure that disinhibition does not occur if chemoprophylaxis was introduced. Education is also important for alleviating any fears of potential adverse affects. For example, informing potential chemoprohylactic users that doxycycline is a widely prescribed antimalarial prophylactic could ease any concerns.42
As yet, no randomized controlled trial has been conducted to evaluate the impact of syphilaxis. This is despite the documented informal use of syphilis chemoprophylaxis over the past 4 decades.43 Based on the predicted population efficacy and the apparent acceptability of the strategy, it is now timely for a chemoprophylaxis clinical trial. On the basis of a number of considerations, doxycycline has emerged as the most promising candidate for this role. Doxycycline has been in clinical use for more than 40 years, receiving Food and Drug Administration approval in 1967. Doxycycline effectively clears T. pallidum44–46 and other organisms,34,35,42 is recommended as a treatment option for syphilis in clinical guidelines in Australia, Europe, and the United States,44,46,47 is administered orally, is inexpensive, and is safe with limited and manageable side effects.48 Many of the side effects can be mitigated with simple measures such as taking the drug in the morning rather than the evening. Other candidates for syphilis chemoprophylaxis include penicillins and azithromycin, but they are inferior to doxycycline in some key aspects. Penicillin G is administered intramuscularly and can occasionally cause severe allergic reactions rendering it unsuitable for use outside a clinical setting, and azithromycin resistance by T. pallidum has been widely reported among gay men in Europe and North America.49
We have begun to develop a multicountry syphilis chemoprophylaxis trial. This randomized double-blind placebo-controlled trial among HIV-infected men at high risk for sexually transmitted diseases will evaluate the impact of doxycycline chemoprophylaxis on the incidence of syphilis and other sexually transmitted infections, and also assess the clinical safety of daily doxycycline and the impact of chemoprophylaxis on sexual risk behavior. As this study demonstrates, using conservative estimates of use-effectiveness in individuals and limited population coverage, oral doxycycline offers promise as an acceptable and effective public health intervention for mitigating syphilis epidemics.
1. Fichtner RR, Aral SO, Blount JH, et al. Syphilis in the United States: 1967–1979. Sex Transm Dis 1983; 10:77–80.
2. De Schryver A, Meheus A. Epidemiology of sexually transmitted diseases: The global picture. Bull World Health Organ 1990; 68:639–654.
3. Peterman TA, Heffelfinger JD, Swint EB, et al. The changing epidemiology of syphilis. Sex Transm Dis 2005; 32(suppl 10): S4–S10.
4. Erbelding E, Rompalo A. Changing epidemiology of syphilis and its persistent relationship with HIV. Curr Infect Dis Rep 2004; 6:135–140.
5. Kerani RP, Handsfield HH, Stenger MS, et al. Rising rates of syphilis in the era of syphilis elimination. Sex Transm Dis 2007; 34:154–161.
6. Bradford DL. Syphilis case-finding in an Australian men's sauna club. Med J Aust 1983; 2:561–564.
7. Golden MR, Marra CM, Holmes KK. Update on syphilis: Resurgence of an old problem. JAMA 2003; 290:1510–1514.
8. Fenton KA. A multilevel approach to understanding the resurgence and evolution of infectious syphilis in Western Europe. Euro Surveill 2004; 9:3–4.
9. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2004 supplement: Syphilis surveillance report. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2005.
10. 2004 Canadian sexually transmitted infections surveillance report. Can Commun Dis Rep 2007; 33(suppl 1):1–69.
11. Chen SY, Gibson S, Katz MH, et al. Continuing increases in sexual risk behavior and sexually transmitted diseases among men who have sex with men: San Francisco, Calif, 1999–2001, USA. Am J Public Health 2002; 92:1387–1388.
12. Lee DM, Chen MY. The re-emergence of syphilis among homosexually active men in Melbourne. Aust N Z J Public Health 2005; 29:390–391.
13. Guo H, Wei JF, Yang H, et al. Rapidly increasing prevalence of HIV and syphilis and HIV-1 subtype characterization among men who have sex with men in Jiangsu, China. Sex Transm Dis 2009; 36:120–125.
14. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: The contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; 75:3–17.
15. Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat Rev Microbiol 2004; 2:33–42.
16. Piot P, Laga M. Genital ulcers, other sexually transmitted diseases, and the sexual transmission of HIV. BMJ 1989; 298:623–624.
17. Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: How much really is known? Sex Transm Dis 2001; 28:579–597.
18. Fisher M, Pao D, Murphy G, et al. Serological testing algorithm shows rising HIV incidence in a UK cohort of men who have sex with men: 10 years application. AIDS 2007; 21:2309–2314.
19. Dukers NH, Spaargaren J, Geskus RB, et al. HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: Using a novel approach for detecting recent infections. AIDS 2002; 16:F19–F24.
20. Grulich AE, Kaldor JM. Trends in HIV incidence in homosexual men in developed countries. Sex Health 2008; 5:113–118.
21. Dougan S, Evans BG, Elford J. Sexually transmitted infections in Western Europe among HIV-positive men who have sex with men. Sex Transm Dis 2007; 34:783–790.
22. Jin F, Prestage GP, Kippax SC, et al. Epidemic syphilis among homosexually active men in Sydney. Med J Aust 2005; 183:179.
23. Mao L, Crawford JM, Hospers HJ, et al. “Serosorting” in casual anal sex of HIV-negative gay men is noteworthy and is increasing in Sydney, Australia. AIDS 2006; 20:1204–1206.
24. Suarez T, Miller J. Negotiating risks in context: A perspective on unprotected anal intercourse and barebacking among men who have sex with men—where do we go from here? Arch Sex Behav 2001; 30:287–300.
25. Suarez TP, Kelly JA, Pinkerton SD, et al. Influence of a partner's HIV serostatus, use of highly active antiretroviral therapy, and viral load on perceptions of sexual risk behavior in a community sample of men who have sex with men. J Acquir Immune Defic Syndr 2001; 28:471–477.
26. Murphy D, Holt M. Responses to syphilis outbreaks among gay and other men who have sex with men: Case studies from the United Kingdom and the United States. Sydney, Australia: Australian Federation of AIDS Organisations, 2009.
27. Ciesielski C, Kahn RH, Taylor M, et al. Control of syphilis outbreaks in men who have sex with men: The role of screening in nonmedical settings. Sex Transm Dis 2005; 32:S37–S42.
28. Hogben M, Paffel J, Broussard D, et al. Syphilis partner notification with men who have sex with men: A review and commentary. Sex Transm Dis 2005; 32:S43–S47.
29. Ashton M, Taylor RH, Gallagher M, et al. An outbreak no longer: Factors contributing to the return of syphilis in Greater Manchester. Sex Transm Infect 2003; 79:291–293.
30. Fenton KA, Wasserheit JN. The courage to learn from our failures: Syphilis control in men who have sex with men. Sex Transm Dis 2007; 34:162–165.
31. Jin F, Prestage GP, Zablotska I, et al. High rates of sexually transmitted infections in HIV positive homosexual men: Data from two community based cohorts. Sex Transm Infect 2007; 83:397–399.
32. Glaser BG, Strauss AL. The discovery of grounded theory: Strategies for qualitative research. Hawthorne, NY: Aldine De Gruyter, 1967.
33. Gray RT, Hoare A, Prestage G, et al. Frequent testing of highly sexually active gay men is required to control syphilis. Sex Transm Dis 2010; 37:298–305.
34. Takafuji ET, Kirkpatrick JW, Miller RN, et al. An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. N Engl J Med 1984; 310:497–500.
35. 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. N Engl J Med 2001; 345:79–84.
36. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001; 23:1296–1310.
37. Omoto AM, Gunn DO, Crain AL. Helping in hard times: Relationship closeness and the AIDS volunteer experience. In: Derlega VJ, Barbee AP, eds. HIV and Social Interaction. Thousand Oaks, CA: Sage, 1998:106–128.
38. Stewart E, Weinstein RS. Volunteer participation in context: Motivations and political efficacy within three AIDS organizations. Am J Community Psychol 1997; 25:809–837.
39. Bebbington AC, Gatter PN. Volunteers in an HIV social care organization. AIDS Care 1994; 6:571–585.
40. Rekart ML, Patrick DM, Chakraborty B, et al. Targeted mass treatment for syphilis with oral azithromycin. Lancet 2003; 361:313–314.
41. Farley TA, Cohen DA, Kahn RH, et al. The acceptability and behavioral effects of antibiotic prophylaxis for syphilis prevention. Sex Transm Dis 2003; 30:844–849.
42. Ohrt C, Richie TL, Widjaja H, et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in Indonesian soldiers. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997; 126:963–972.
43. O'Keefe BG. Medicine at war: Medical aspects of Australia's involvement in Southeast Asia 1950–1972. Sydney: Australia: Allen and Unwin, 1994.
44. Ghanem KG, Erbelding EJ, Cheng WW, et al. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 2006; 42:e45–e49.
45. Onoda Y. Therapeutic effect of oral doxycycline on syphilis. Br J Vener Dis 1979; 55:110–115.
46. Wong T, Singh AE, De P. Primary syphilis: Serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med 2008; 121:903–908.
47. Parkes R, Renton A, Meheus A, et al. Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe. Int J STD AIDS 2004; 15:73–88.
48. Smith K, Leyden JJ. Safety of doxycycline and minocycline: A systematic review. Clin Ther 2005; 27:1329–1342.
49. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum
in the United States and Ireland. N Engl J Med 2004; 351:154–158.