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Serological Response to Syphilis Treatment in HIV Infected and Uninfected Patients Attending STD Clinic at Johns Hopkins
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Epub, Jan 2007. STI Online First, published on August 30, 2006 as 10.1136/sti.2006.021402
Khalil G. Ghanem1, Emily J. Erbelding1, 2, Zachary S. Wiener1, and Anne M. Rompalo1
1Johns Hopkins University School of Medicine, Baltimore, MD; 2 Baltimore City Health Department.
".....Our evaluation of outcomes in a clinic cohort of syphilis patients highlights two important findings: (1) HIV infected patients with early stage syphilis are more likely to experience serological failure following syphilis therapy than HIV uninfected patients; (2) routine follow-up of serologic response following therapy is equally poor in both groups: lack of follow-up data on nearly 65% of HIV infected and 77% of HIV uninfected patients treated for syphilis. .... In our study, there was a trend for increased failure in late latent syphilis/ unknown duration among the co-infected as compared to the HIV negative group (18.6% vs. 7.1%, respectively). The relatively few HIV uninfected patients with late stage disease may have limited the power of our study.... As in many syphilis series, it is difficult to ascertain whether a patient has experienced treatment failure or re-infection...."
Abstract
Background: HIV+ patients treated for syphilis may be at increased risk for serological failure. We compared number of follow-up serologies and serological response to therapy between HIV infected and uninfected patients attending two STD clinics.
Study Design: We reviewed existing records from patients known to be HIV+ who were diagnosed and treated for syphilis at the public STD clinics in Baltimore, Maryland between 1992 and 2000. Results of their serological follow-up were compared to those of clinic patients whose HIV test was negative at the time of syphilis treatment. We defined failure as lack of a 4-fold drop in RPR titer by 400 days post-treatment, or a 4-fold increased titer between 30 and 400 days.
Results:
Of 450 HIV+ syphilis patients, 288 (64%) did not have documented follow-up serologies and 129 (30%) met the inclusion criteria; 168 of 1000 (17%) known HIV- patients were similarly eligible.
There were 22 failures in the HIV+ group and 5 failures in the HIV- group (p<0.001).
The median times to successful serological responses in the HIV+ and HIV- groups were 278 days (95% CI 209-350) and 126 days (95% CI: 108-157), respectively (p<0.001).
In a multivariable Cox proportional hazards model there was an increased risk of serological failure among the HIV+ group (HR 6.0, 95%CI: 1.5-23.9; p=0.01).
Conclusion: HIV+ patients treated for syphilis may be at higher risk of serological failure. Despite recommendations for more frequent serological follow-up, a majority of patients did not have documentation of serological response following standard therapy for syphilis.
Introduction
The interaction between syphilis and HIV is complex and not fully understood. Syphilis prevalence is higher in patients with HIV infection 1-3, HIV has been identified in primary syphilitic ulcers 4, and HIV viral load has been documented to increase during primary and secondary syphilis 5, 6 thus confirming the biological plausibility of epidemiologic observations that syphilis facilitates
the transmission and acquisition of HIV. Although dramatic and unusual presentations of syphilis have been reported among HIV co-infected individuals 7, 8, larger studies report no significant differences in the presentation of syphilis and its response to therapy 9. A troubling observation in the largest treatment trial of early syphilis was higher serological failure rates among HIV-infected compared to HIV uninfected patients after treatment for primary or secondary syphilis, but the reverse after treatment for early latent syphilis, and an overall serologic failure rate of 14% at one year 10. In a recent cohort study which compared syphilis serologic titer responses after treatment in Lima, Peru 11, HIV status (N=11) had no effect on rate of serologic response. Regardless of HIV status, 17% of patients required additional treatment. Recent data also indicate higher rates of neurosyphilis among HIV-infected patients but do not clarify if this is a result of more rapid progression of syphilis in HIV or therapeutic failure 12. Syphilis treatment regimens at this time do not differ for HIV-1 infected patients but the Centers for Disease Control and Prevention (CDC) recommends more aggressive follow-up in those who are co-infected 13. Our goal was to compare number of follow-up serologies and serological response to syphilis therapy between HIV infected and uninfected patients in a clinical setting with a high prevalence of both infections.
Results
There were 3,607 records documenting primary, secondary, early latent or late latent syphilis/syphilis of unknown duration between January 2, 1992 and December 31, 2000. We excluded 196 (5.4%) records documenting primary syphilis based on negative serologies but positive darkfield microscopic findings, and 1613 (44.7%) records without documentation of HIV serostatus leaving records of 450 (12.5%) HIV infected patients and 1348 (37.4%) HIV uninfected
patients.
Of the HIV infected, 286 (63.6%) had no documented follow-up serologies available, and 35 (7.8%) had follow-up serological titers obtained >400 days after treatment. Of 1348 HIV uninfected patients, 1000 patients were randomly selected. 768 (76.8%) did not have documented follow-up serologies available, and 64 (6.4%) had follow-up serological titers obtained >400 days
after treatment. This left records from 129 HIV infected and 168 HIV uninfected patients for inclusion.
Baseline characteristics of eligible patients and those excluded are reported in Table 1. HIV infected patients were more likely to report having had >5 sexual partners in the past month (p<0.001), have late latent/unknown duration syphilis (p<0.001), and have lower (<1:16) RPR titers (p<0.01). HIV uninfected patients were more likely to report known contact with a syphilis-infected partner (p<0.001) and more likely to report a past history of syphilis infection (p<0.01). HIV infected patients had more follow-up RPR serologic values than uninfected patients (2.1 vs. 1.5, p<0.001). 53 of 129 HIV+ patients at baseline had 5 or more sexual partners, while 20 of 168 HIV-negatuve patients had 5 or more sexual partners.
There were 29 serological failures among the HIV+ group and 7 serological failures among the HIV-negative group. After reviewing DIS records, 7 failures among the HIV co-infected group and 2 failures among the HIV uninfected group were documented to be due to reinfection and were excluded from the analysis. The remaining patients with serological failure are described in Table 2.
There were 22 failures among the HIV positive group (17%) and 5 failures among the HIV negative group (3%) (p<0.001). When stratified by syphilis stage, 4 of 32 (12.5%) HIV infected patients with early syphilis had serological failure as compared to 4 of the 154 (2.6%) HIV uninfected (p<0.01); 18 of 97 (18.6%) HIV positive patients with late latent/unknown duration syphilis had evidence of serological failure as compared to 1 of 14 (7.1%) uninfected patients (p=0.3). Among patients with early stage disease, 3.1% (1/32) of HIV infected and 1.3% (2/154) of uninfected patients failed due to lack of a four-fold titer drop (p=0.5) and 9.4% (3/32) of HIV infected and 1.3% (2/154) of uninfected patients failed due to four-fold titer increase (p<0.05). Among patients with late latent disease, 11.3% (11/97) of HIV infected and 7.1% (1/14) of uninfected patients failed due to lack of a four-fold titer drop (p=0.6) and 7.2% (7/97) of HIV infected and 0% (0/14) of uninfected patients failed due to four-fold titer increase (p=0.4).None who failed showed evidence of an early interval drop in titers followed by a four-fold rise ("relapsers").
Kaplan-Meier curves comparing time to serological failure between HIV infected and uninfected patients are shown in Figure 1 stratified by syphilis stage. Time to failure was significantly longer in the HIV+ group with early syphilis; this difference was not seen with late latent infection. In a multivariable Cox Proportional Hazards model adjusting for age, past history of syphilis, baseline RPR titer, number of follow-up RPR titers, type of treatment (doxycycline vs.
benzathine penicillin G), and syphilis stage, the risk of serological failure was higher among the HIV-infected patients (HR 6.0, 95%CI: 1.5-23.9). There was a lower risk of failure among those whose baseline RPR titers were 1:64 (HR 0.03, 95% CI: 0.001-0.8).
Overall, among patients with documented serological response to therapy (Figure 2), the median time to response between the HIV infected and uninfected patients was 278 days (95% CI: 209-350) and 128 days (95% CI:108-157), respectively (p<0.001). When stratified by syphilis stage, there was no difference in time to serological responses between the two groups with early syphilis
(logrank p=0.3) [median time to response: 168 days (95%CI: 77-350) vs. 126 days, (95%CI: 108- 155), respectively]. However, HIV infected patients with late latent infection had a slower response time to therapy than HIV uninfected patients (logrank p=0.03) [median time to response: 342 days (95%CI: 248-370) vs. 138 days (95%CI: 24-341), respectively].
Discussion
Our evaluation of outcomes in a clinic cohort of syphilis patients highlights two important findings: (1) HIV infected patients with early stage syphilis are more likely to experience serological failure following syphilis therapy than HIV uninfected patients; (2) routine follow-up of serologic response following therapy is equally poor in both groups.
Our findings in early syphilis are consistent with those reported by others 10, 15-17. In the most rigorously designed study 10, HIV co-infected patients with primary syphilis were more likely to experience serological failure than their HIV-negative counterparts (22% vs. 8%, respectively) six months following therapy as well as a trend towards increased odds of failure among co-infected
patients with secondary syphilis (23% vs. 10%).
In our study, there was a trend for increased failure in late latent syphilis/ unknown duration among the co-infected as compared to the HIV negative group (18.6% vs. 7.1%, respectively). The relatively few HIV uninfected patients with late stage disease may have limited the power of our study to detect such differences. In the multivariable Cox Proportional Hazards model, stage of
syphilis was not an independent predictor of failure. The distinction between serological failure and clinical failure is an important one to make. Of the patients who had evidence of serological failure and who were followed at the STD clinics (10/27), none had documented evidence of clinical failure.
Although some studies reported a slower serological response in HIV infected patients compared to uninfected patients 10, 16 other studies did not 18. Thus, higher failure rates in HIV-infected patients may be the result of slower declines in nontreponemal serologies rather than a lack of response to therapy. Among the patients who failed in our study, equal proportions in the HIV positive and negative groups failed because of a lack of a four-fold drop in serological titers
suggesting that the higher failure rates among HIV infected patients that we observed were probably not due to a slower response time, at least not at 12 months after treatment.
The second important finding in our study is the lack of follow-up data on nearly 65% of HIV infected and 77% of HIV uninfected patients treated for syphilis. Similar lack of compliance with post-treatment serological follow-up has been reported in the United Kingdom 19 It is possible that some patients did not have follow-up titers documented in the statewide registry because they died,
moved out of the state of Maryland, or they seroreverted (and thus, mandatory reporting by laboratories and physicians of positive serologies does not apply). In HIV negative patients, RPR seroreversion at 3 months and 12 months have been documented to occur in about 13% and 44% of patients with a first episode of primary syphilis, 0.7% and 22% of patients with secondary syphilis, and 3% and13% of patients with early latent syphilis 20, respectively.
These data suggest that although seroreversion could account for some of the loss to follow-up, a significant number of syphilis patients are not being routinely monitored. Given the high rates of serologic failure in HIV co-infected patients and risks of clinical consequences related to such failures, improving the mechanisms to assure more consistent follow-up is prudent to avoid long-term sequelae. One possible solution is to expand the role of DIS to include follow-up of co-infected patients after treatment. This initiative in a city with a high STD burden such as Baltimore is prohibitively expensive.
Our study has several limitations. The eligible patients represented a fraction of the patients diagnosed with syphilis, thus, selection bias is of concern. We have provided data on patients who were excluded from the study. These patients were more likely to be male, and report fewer sex partners in the last month at the time of evaluation as compared to both the HIV infected and uninfected groups. Whether these differences impact outcome is unknown. Nearly 45% of patients were excluded because they did not have an HIV test documented in our clinic database. HIV testing is routinely offered to all patients who attend STD clinics in Baltimore. Only 19% refused HIV testing at the time of clinic visit and had reported not being tested in the previous 6 months. The remaining patients refused HIV testing but reported having been tested elsewhere in the previous 6
months. As in many syphilis series, it is difficult to ascertain whether a patient has experienced treatment failure or re-infection. This is especially important because HIV-infected patients may be linked to sexual networks with a higher prevalence of syphilis creating a bias toward higher rates of failure.
In our study, for example, more co-infected patients with early syphilis failed because of a four-fold rise in titers suggesting potential re-infection. In order to classify failures appropriately, we reviewed the DIS charts of all patients who fit the definition of treatment failure and we excluded all those who were not interviewed or who were felt by trained DIS to have been re-infected (5 HIV+ and 2 HIV- patients were excluded) based on the interviews of the index case and follow-up of their sex partners.
HIV-infected patients had more follow-up serological titers than HIV negative patients. This may have lead to 2 potential biases: first, HIV+ patients had more opportunity to be diagnosed as treatment failures because they had more follow-up serologies. To minimize that, we adjusted for number of follow-up titers in the multivariable model. Second, HIV-infected patients had more follow-up titers which may have underestimated time to serological response in the HIV-negative
group (fewer serologies leading to an apparent slower response time). This, however, would bias our results towards the null and strengthen our findings.
Finally, because this study was performed at an STD clinic, CD4 cell counts and HIV viral load determinations were not available. Thus, whether the degree of immunosuppression enhances failure cannot be determined. Previous
studies, however, suggest that CD4 count does not correlate with serological failure 6, 10.
In summary our data suggest that HIV-infected patients with syphilis are more likely to experience serological failure consistent with findings in several studies including a randomized trial. More important is that a majority of these co-infected patients are not returning for timely follow-up serologies to document therapeutic response. Efforts to ensure more consistent serologic follow-up among patients treated for syphilis, especially those who are HIV infected, are warranted.
Methods
Data Collection and Definitions
We analyzed electronic data records from patients diagnosed with primary, secondary, early latent and late latent syphilis who attended the Baltimore STD clinics between 1992 and 2000. Diagnoses were made by trained clinicians based on published criteria 14. Rapid plasma reagin (RPR) test was used and reactive specimens were confirmed using the fluorescence treponemal antibody absorption test (FTA-ABS). Primary syphilis with nonreactive serologies at
the time of treatment was excluded as this study focused on serological responses. This study was approved by the institutional review boards of the participating institutions.
Demographics, behavioral risks, syphilis stage, and treatment were collected on
standardized clinical encounter forms, then scanned into a database, and linked to laboratory results. We also reviewed additional serological test results from a statewide syphilis registry that included results from public and private testing venues throughout the state of Maryland.
Patients were HIV uninfected if they had a nonreactive HIV test at the time of syphilis diagnosis or any visit thereafter and HIV infected if a test was reactive at or before the time of syphilis diagnosis. Records from patients whose HIV serologies were undocumented were excluded. Records with no HIV result documented, no initial RPR titer, or no follow-up titer within 400 days of treatment were also excluded.
Serological failure was defined as a four-fold rise in RPR titers 30 - 400 days after treatment or lack of a four-fold drop in RPR titers at 270 -400 days and no evidence of reinfection based on disease intervention specialists' (DIS) records. These are trained public health workers who are dispatched to find and interview patients who have positive syphilis serologies. The records include detailed behavioral information on the index patient and their sex partners. Those with low pretreatment baseline titers (≦1:2) who did not serorevert and had no clinical evidence of failure were not considered serological failures. We used the 400 day cutoff based upon preliminary data analysis indicating capture of most patients returning for their 12 month follow-up serologies. Similarly, although we were interested in serological failures occurring one year following therapy, records with follow-up serologies obtained between 270 days and 400 days post therapy met our criteria. DIS records were reviewed on all patients who did not respond to therapy and those patients whose failure was deemed secondary to reinfection were excluded.
We compared the time to serological response between HIV infected and uninfected patients. Time to serological response was defined as the earliest date following therapy documenting a four-fold drop in RPR titers. Subjects whose titers had not dropped four-fold and whose last follow-up titers were less than 270 days from the date of treatment were censored at the date of last follow-up serology.
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