# Presentation: 523523

## Successful prevention of syphilis infection with azithromycin in both HIV-negative and HIV-positive individuals, San Francisco, 1999-2003. 

- J. D. Klausner,1,2 K. Steiner,1 _R. Kohn_11San Francisco Dept Public Health, San Francisco, CA 2University of California, San Francisco, San Francisco, CA.

**Notes:**
I would like to recognize my co-authors on this study.  Dr. Jeff Klausner had the basic idea for the study, and has implememented the use of azithromycin in San Francisco for treatment of syphilis.  Kate Steiner wrote the abstact and helped with some of the statistics.

## Background: Syphilis trends in San Francisco

**Notes:**
Syphilis had reached all-time lows in San Francisco by the end of the 90’s, but had mostly leveled off.  We were looking for new approaches as part of the syphilis elimination campaign.  And very soon we saw large increases in the number of cases, which presented new challanges for our efforts at disease control.

## Background: Current syphilis epidemic in San Francisco

**Notes:**
Starting in 1999, we saw large increases in the number of syphilis cases in San Francisco, and, like many other parts of the country,  this increase was almost completely among gay and bisexual men.  

## Background:Previous studies on azithromycin and syphilis

- Hook EW, Stephens J, Ennis DM, *Ann Intern Med, *1999
- randomized trial of 1 gram azithromycin vs. 2.4 mu benzathine penicillin for incubating disease
- no reactive FTA-ABS at 3 months in either group
- Hook EW *et al*., *Sex Trans Dis*, 2001
- RCT of azithromycin vs. benzathine penicillin for syphilis cases
- 2 grams of azithromycin as effective as benzathine penicillin for treating disease

**Notes:**
Research by Dr. Ned Hook published in 1999 showed that one gram of azithromycin was as effective at treating incubating syphilis as the standard treatment of 2.4 million units of benzathine penicillin.  The advantage of azithromycin was that it was taken orally, while benzathine penicillin was administered n a shot.  Dr. Hook noted that use of azithromycin has “fewer barriers in non-clinical settings”

## Background:Syphilis treatment in San Francisco

- Contacts: new cases versus “epi treatment”
- 2.4 mu benzathine penicillin G I.M. (“bicillin”)
- 100 mg doxycycline P.O. BID for 14 days
- 1 gram azithromycin P.O.
- Field-delivered therapy with Azithromycin began March, 1999

**Notes:**
In San Francisco, when treating contacts to syphilis patients we make the standard distinction between contacts who have a reactive syphilis test and those who test is nonreactive.  Contacts who are reactive are new cases; those who are nonreactive, and possibly incubating syphilis, are called “epi treatment”.

The standard epi-treatment for syphilis at City Clinic was 2.4 million units of benzathine penicillin, commonly referred to as “bicillin.”  For patients alleric to penicillin, we had used two weeks of doxycycline, but we switched to azithromycin.

In 1999 we began to allow disease control investigators to use azithromycin to treat syphilis contacts in the field.  The disease control investigators would always get a blood specimen for a syphilis test, however, so that we could determine whether the contact was a new case and needed further treatment.

## Objective

- Compare observed success in treating incubating syphilis using azithromycin to success with other treatments in order to justify continued use of azithromycin

## Methods:San Francisco STD Registry

- STD clinic medical record data
- Reported morbidity and reactive STS
- Interview data and field activity
- Screening data

**Notes:**
This analysis made use of our integrated STD registry.  We have a single database for most all data collected by our program, including medical record data from our STD clinic, reported morbidity and syphilis test result, all our field investigation data, and testing data from our screening program.  All data for each patient is tied together as it is entered, so no matching was necessary.

## Methods: Sample

- Data from 1999 through 2003
- Non-reactive RPR or VDRL with any syphilis treatment (n=3812)
- Follow-up titer between 30 and 90 days after initial titer (n=151)

**Notes:**
We included data from the registry from 1999, when we began using azithromycin in the field, through the end of last year.  We started with all patients with an non-reactive syphilis test who had been epi-treated on the test date.  We then looked for follow-up titers between one month and three months after the test date.  Contacts are told to come back at one month and three months to make sure they were treated adequately.

## Methods: Measurements

- Outcome: any reactive titer defines treatment failure
- Biological false positives excluded from analysis
- HIV status measured from multiple sources, including self-reported status

**Notes:**
We examined the proportion of contacts who had any subsequent reactive syphilis test in that time frame.  Patients with nonreactive confirmatory tests were excluded from the analysis.  We looked at HIV status of the contacts using self-reported status and HIV testing results from City Clinic.

## Results:All patients

**Notes:**
There were four contacts with reactive follow-up tests, three treated with axithromycin, and one treated with bicillin.  The proportion of failures among contacts treated with bicillin was actually higher than for azithromycin, but the confidence limits on these proportions were so wide that no differences were statitistically significant.

Note that these numbers are different than what we put in our abstract, since they include all of 2003.

## Results: By HIV Status

**Notes:**
There were 26 patients whose HIV status was not known.  No failures were observed among HIV-positive patients.  

I did not include the confidence limits here because they were no more impressive than in the previous slide.

## Conclusions

- Failure rate for azithromycin was not significantly greater than rate for bicillin
- Since no resistance to bicillin has been documented, apparent treatment failures likely indicate re-exposure
- Success in treatment did not vary between HIV-negative and HIV-positive clients

## Limitations

- No way to distinguish treatment failure from re-exposure
- Not all exposed will develop disease
- No randomization
- penicillin allergies
- field versus clinic
- Small number of follow-up titers
- Wide confidence limits for negative results

**Notes:**
The fact that 2.3 percent of patients treated with azithromycin had a reactive follow-up test does not mean that we prevented disease for the other 97.7 percent of contacts.

All the patients treated with bicillin were seen in the clinic, and there may differences between those patients who come in when referred to the clinic and those patients we treat in the field because they did not come in.

We need to recognize that there was not much power here to detect even substaintial differences between treatments, and lack of evidence of a difference is not the same as evidence of a lack of difference.

## Limitations

- No power to assess temporal trends
- Azithromycin epi-treatment failures:
- November 2002
- April 2003
- July 2003
- Bicillin epi-treatment failure:
- April 1999

**Notes:**
It is worth noting that all three azithromycin failure happened toward the end of the four-year study period, while the bicillin failure was at the beginning.

## Further research

- Another randomized trial of azithromycin vs. bicillin
- HIV-positive clients only
- San Francisco & Los Angeles
- Five years later than 1999 study by Hook

**Notes:**
We are planning a new study which will include 500 HIV-positive contacts from San Francisco and Los Angeles to try to replicate the results of Dr. Hook’s 1999 study, and see if azithromycin works just as well in the population, and five years later.

## Thank you ...