Our data suggest that the treatment of HIV infection with HAART and the use of macrolides improve syphilis serologic responses in coinfected patients. These findings are notable, because 16% of all patients who have syphilis are also HIV infected [1
], and coinfected patients may be at an increased risk for serologic failure [4
The impact of HAART on the response of syphilis patients was consistently observed independent of the type or timing of serologic failure (). Whether this is simply the result of better immunologic responses among those who received HAART is difficult to ascertain, because of the significant serologic benefits observed even in those who did not manifest an overt immunologic response to HAART. However, even when patients who receive HAART do not experience CD4 cell reconstitution, there are data to suggest that there are immunologic benefits [18
]. An alternate behavioral hypothesis for the effect of HAART is that individuals who receive HAART define a more adherent and compliant behavior group that may be less likely to be reexposed to risky partners and may be more likely to practice safe sex. A meta-analysis by Crepaz et al. [19
] suggested that the use of HAART in HIV-infected patients did not result in increased sexual risk-taking behaviors, even in cases in which the patient achieved an undetectable viral load.
Macrolides have well-documented treponemicidal activity [20
], but the recent development of resistant Treponema pallidum
strains has limited their widespread use [22
]. In our cohort, most macrolide use was for opportunistic infection prophylaxis. Thus, the observed serologic benefits of macrolides may have been attributable to the enhancement of the incomplete treponemicidal activity of penicillin, or possibly it was attributable to postexposure prophylaxis, because the effects of macrolide use appeared to extend across all groups (). Previous approaches to treatment of HIV-infected patients who had syphilis have focused on evaluating the efficacy of more-intensive short-term treatment. A multicenter, randomized, controlled trial showed that enhanced therapy for early syphilis did not lead to improved serologic or clinical outcomes at 1 year [6
]. Enhanced therapy in that study consisted of a 10-day course of oral amoxicillin with probenecid. Whether macrolide exposure might exert serologic benefit through enhanced CNS penetration, compared with oral β
], or by extending the duration of therapy is unclear. The effects of macrolides in our study were observed in individuals with more-advanced immunosuppression. One explanation is that those patients with preserved cellular immunity are better able to control syphilis infection and are, thus, less dependent on enhanced macrolide therapy; alternatively, the number of patients with preserved immune responses who did receive macrolides was relatively small, thus limiting our ability to detect a beneficial effect in that group.
The clinical significance of RPR seroreversion in the penicillin era is unclear. In the prepenicillin era, patients who had early syphilis who did not manifest nontreponemal-specific test reversions at the end of therapy were at an increased risk for experiencing treatment failure [24
]. In the pre-HIV penicillin era, documented treatment failures were exceedingly rare [25
], but RPR seroreversions were relatively common after penicillin therapy. Studies in the pre-HIV penicillin era documented close to a 100% rate of RPR seroreversion 1–2 years (depending on the stage of syphilis and the duration of symptoms) after penicillin therapy (4.8 MU of benzathine penicillin G) among patients with primary and secondary syphilis [26
]. During the early years of HIV, Romanowski et al. [28
] demonstrated that up to 72% of patients with an initial episode of primary syphilis and 56% of patients with secondary syphilis experienced RPR seroreversions at 36 months after therapy (usually, 2.4 MU of benzathine penicillin G). The influence of HIV on the rate of seroreversion could not be assessed. In our study, a smaller fraction of patients experienced RPR seroreversion () despite a relatively long follow-up period. This raises several interesting questions. Is the decreasing incidence of seroreversion in the penicillin era the result of lower dosages of penicillin or of immunosuppression due to HIV infection? Does the lack of seroreversion (especially among patients who have early syphilis) increase the subsequent risk of treatment failure? In our study, only 11.5% of patients who experienced seroreversion experienced subsequent serologic failure. Overall, there was a non–statistically significant 52% reduction in the risk of serologic failure among patients who experienced RPR seroreversion, compared with those who did not. Subgroup analysis suggests that this was mostly driven by patients who experienced early serologic failure, suggesting that seroreversion may impact treatment failure but not reinfection. The corollary is whether enhanced syphilis therapy with the goal of RPR seroreversion (rather than a 4-fold decrease in RPR titers) in HIV-infected patients would result in improved serologic outcomes.
This study has several limitations. First, our endpoint of serologic failure included patients who experienced either treatment failure or reinfection. In any syphilis study that lacks behavioral or network data, the distinction between these 2 events is very difficult to make. We did not see an impact of HIV transmission risk group on the rate of serologic failure, but this behavioral information may be too crude to detect meaningful differences. We further analyzed the data using both the type of serologic failure and the timing of failure, because both of these approaches have been used to differentiate between treatment failure and reinfection. We did observe consistent findings of improved serologic outcomes with the use of HAART and macrolides across these groups, which suggests that these findings are likely to be clinically meaningful.
Second, serologic response after syphilis therapy in HIV-infected patients may be slower than serologic response in non–HIV-infected patients [7
]. The Centers for Disease Control suggests a relatively wide window of time for determining serologic nonresponse: 6–12 months after treatment of early syphilis and 12–24 months after treatment of late latent infection [29
]. In our observational study, the median time to retreatment for early syphilis was 483 days, and it was 528 days for late latent infection. There may have been fewer patients classified as nonresponders if clinicians had waited the full 730 days before treating the late latent nonresponders again.
Third, we did not have data concerning penicillin and cephalosporin use during follow-up other than the use of oral penicillin, amoxicillin, and amoxicillin plus clavulanic acid. This may have biased our combined penicillin and doxycycline data towards a null finding. Furthermore, some of the data on medication use was obtained from patient self-reports. Serologic testing was not performed in batches; thus, variation in laboratory test performance may have led to misclassifications of serologic failure. However, we expect this misclassification to be nondifferential across groups. Changes in RPR titers may be a manifestation of abnormal B cell dysregulation associated with HIV infection rather than with serologic failure [30
]. Our population represented a heterogeneous group with respect to HIV risk factors. Whether our findings would be generalizable to other populations is unknown. Finally, the number of RPR serologic tests was consistent among all patients, thus the potential for outcome identification bias (i.e., less frequent serologic testing among individuals with advanced immunosuppression may lead to fewer opportunities to detect serologic failure) was limited.
The interaction between syphilis and HIV infection is complex. In the future, a better understanding of the relationship between syphilis serologies and host immunity may help determine whether current treatment targets should be modified. Currently, the only difference in syphilis treatment recommendations between HIV-infected and non–HIV-infected patients is a more aggressive follow-up schedule for serologic testing in HIV-infected patients [29
]. Unfortunately, this is not always easy to achieve in clinical practice, because follow-up is often lacking [7
]. On the basis of our data, coupling the recommendation of more-frequent serologic follow-up of coinfected patients to aggressive HIV infection management—including the use of HAART and the use of macrolides for opportunistic infection prophylaxis, particularly among patients who are more severely immunosuppressed—may improve syphilis serologic responses.