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Azithromycin Treatment Failure for Chlamydia trachomatis Among Heterosexual Men With Nongonococcal Urethritis

Kissinger, Patricia J. PhD; White, Scott MS, MPH; Manhart, Lisa E. PhD; Schwebke, Jane MD; Taylor, Stephanie N. MD; Mena, Leandro MD, MPH; Khosropour, Christine M. PhD; Wilcox, Larissa MS; Schmidt, Norine MPH; Martin, David H. MD

doi: 10.1097/OLQ.0000000000000489
Original Studies
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Background Three recent prospective studies have suggested that the 1-g dose of azithromycin for Chlamydia trachomatis (Ct) was less effective than expected, reporting a wide range of treatment failure rates (5.8%–22.6%). Reasons for the disparate results could be attributed to geographic or methodological differences. The purpose of this study was to reexamine the studies and attempt to harmonize methodologies to reduce misclassification as a result of false positives from early test-of-cure (TOC) or reinfection as a result of sexual exposure rather than treatment failure.

Methods Men who had sex with women, who received 1-g azithromycin under directly observed therapy for presumptive treatment of nongonococcal urethritis with confirmed Ct were included. Baseline screening was performed on urethral swabs or urine, and TOC screening was performed on urine using nucleic acid amplification tests. Posttreatment vaginal sexual exposure was elicited at TOC. Data from the 3 studies were obtained and reanalyzed. Rates of Ct retest positive were examined for all cases, and a sensitivity analysis was conducted to either reclassify potential false positives/reinfections as negative or remove them from the analysis.

Results The crude treatment failure rate was 12.8% (31/242). The rate when potential false positives/reinfections were reclassified as negative was 6.2% (15/242) or when these were excluded from analysis was 10.9% (15/138).

Conclusions In these samples of men who have sex with women with Ct-related nongonococcal urethritis, azithromycin treatment failure was between 6.2% and 12.8%. This range of failure is lower than previously published but higher than the desired World Health Organization's target chlamydia treatment failure rate of < 5%.

Methods for 3 studies reporting diverse treatment failure rates for Chlamydia trachomatis using 1-g azithromycin were harmonized and data were reanalyzed. Treatment failure was 6.2% to 12.8%, higher than acceptable standards.

From the *Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA; †Department of Epidemiology, ‡Department of Global Health, University of Washington, Seattle, WA; §Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; ∥Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA; and ¶Department of Medicine, University of Mississippi Medical Center, Jackson, MS

Acknowledgments: LA CaTS Center grant 1 U54 GM104940.

This work was financially supported by NIAID R56AI085081, NIAID R01AI097080, DMID N01A140073C, NIAID U19-AI31496, NIAID U19AI31448, R01 AI072728 and 1 U54 GM104940.

Conflict of interest: None declared.

Correspondence to: Patricia J. Kissinger, PhD, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, SL-18 1440 Canal Street, Suite 2004, New Orleans, LA 70112. E-mail: kissing@tulane.edu.

Received for publication April 5, 2016, and accepted May 27, 2016.

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Background and Significance

The rate of retesting positive after treatment for Chlamydia trachomatis (Ct) infection is high in both men and women with rates of 11%1 and 10.7%,2 respectively. Among women, persistent or recurrent infections can cause serious sequelae including ectopic pregnancy, pelvic inflammatory disease, infertility, and increased susceptibility to human immunodeficiency virus infection.2,3 Among men, persistent or recurrent infections also increase the chance of human immunodeficiency virus acquisition and transmission and increase the likelihood of Ct transmission to sexual partners.4,5

Azithromycin 1 g is one of the first-line treatments recommended by the Centers for Disease Control and Prevention for the treatment of uncomplicated Ct, yet there is growing concern that this treatment has become less effective.1 A meta-analysis conducted in 2002 found the cure rate for azithromycin to be 97%.6 A more recent meta-analysis, conducted in 2014, found the pooled cure rate to be 94%.7 These data suggest that azithromycin treatment failure may be higher than originally thought. In the discussion sections of both meta-analyses, however, the authors indicate that there were methodological limitations to the studies they used as inputs for the meta-analysis which may have impacted their results.

Three recent prospective studies reported repeated detection of C. trachomatis (Ct) in men after treatment with the recommended 1-g dose of azithromycin ranging widely from 5.8% to 22.6%.8–10 Differences in rates could be attributed to test of cure (TOC) measurement issues, variable rates of posttreatment sexual exposure, or geographic variability in azithromycin susceptibility.

False-positive tests can occur if nucleic acid amplification tests (NAAT) are done before remnant Ct DNA had cleared from urethral secretions. The time required for Ct nucleic acid to clear from genital secretions posttreatment has not been clearly determined. The Centers for Disease Control and Prevention recommends waiting for 3 weeks to retest persons with sexually transmitted infections using NAAT11 and several studies corroborate this recommendation.12–14 Therefore, positive NAAT tests done before 3 weeks could actually be false positives.

A positive test after treatment could be indicative of reinfection (as the result of sexual exposure to an untreated baseline partner or a new partner) rather than treatment failure (which implies ineffective antimicrobial therapy in the case of a drug such as azithromycin which is given as a single directly observed dose).15 Two separate studies have found that 12% of men with nongonococcal urethritis (NGU) engaged in sex before they were sure their partner took the medication.16,17 A positive test posttreatment could also be the result of infection from a new partner. Sexual exposure soon after treatment is, therefore, a potential source of error when estimating rates of treatment success.

The purpose of this study was to reexamine the aforementioned 3 studies and attempt to harmonize methodologies to reduce misclassification as a result of false positives from early TOC and sexual exposure during follow-up (from an untreated partner or infected new partner).

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METHODS

Data from 3 studies in geographically distinct areas were obtained from the principal investigators under a data sharing agreement and reanalyzed.8–10 The secondary data analysis was approved by the institutional review boards of all participating institutions. Common inclusion criteria for all studies were English-speaking men who had sex with a women in the last 2 to 3 months, attended an sexually transmitted disease clinic, were diagnosed with NGU, and had a positive test for Ct in urine or urethral swab test using the Aptima Combo 2 assay (Hologic/Gen-Probe Inc.) Analyses were limited to men who were treated with 1 g azithromycin under direct observation therapy and retested posttreatment using the same assay for a urine specimen. Partner referral for treatment was conducted at all sites. Men were interviewed at both baseline and follow-up to elicit information about sexual exposure/reexposure. Differences in methods are described below and summarized in Table 1.

TABLE 1

TABLE 1

Study 18 was a cohort study conducted from January 2011 to July 2013 in New Orleans, Louisiana and Jackson, Mississippi. Men were at least 18 years old and had sex with at least 1 woman in the 2 months before enrollment. Men completed surveys regarding sexual behavior via computer assisted self-administered interviews (CASI) at baseline and follow-up. Partner treatment/notification followed the clinical standard of care (ie, referral cards were provided to the patient to give to their partners). Men who had a Ct+ result at the baseline visit were asked to return for a follow-up visit approximately 4 to 6 weeks after treatment to be retested for Ct and to complete a behavioral CASI survey (n = 160).

Study 29 was a randomized clinical trial (RCT) conducted between January 2007 and July 2011 in Seattle, Washington. Men were at least 16 years old and were interviewed by CASI at baseline and follow-up. Men were asked to return for follow-up after 3 weeks (2- to 5-week window) where a urine specimen was retested using NAAT and reinterviewed via CASI. Only men in the 1-g azithromycin arm of this study and who had sex with women were included (n = 29).

Study 310 was an RCT conducted between November 2006 and April 2009 in 4 cities: Birmingham, Ala; Baltimore, Md; Chapel Hill, NC, and New Orleans, La. Men were between 16 and 45 years old, had sex with at least 1 woman in the 3 months before enrollment, were asked to return to the clinic for 2 follow-up visits (1 at 2 weeks and 1 at 5 weeks after treatment), and were counseled to use condoms with all partners during the follow-up period. In this study, only the first follow-up visit postbaseline data was analyzed because those with positive tests were retreated. Only men in the 1-g azithromycin arm were included. At baseline and each follow-up visit, information regarding recent sexual activity was elicited through face-to-face surveys (n = 53).

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Data Analysis

Data analysis was conducted using SAS 9.3 and using χ2 and Fisher exact tests to determine statistical significance (P < 0.05). Data from all sites were reanalyzed together to calculate a crude rate of retest positivity. Test of cure Ct rates were compared by the presence or absence of symptoms at baseline, time of retesting (ie, before 21 days vs 21+ days), by city, and by study.

A sensitivity analysis was conducted to assess the potential impact of misclassification from false positives that could result from testing before 21 days and from reinfection as a result of sexual exposure via unprotected sex with a baseline or new partner. For this analysis, positives were reclassified as negative if they were tested before 21 days posttreatment completion and/or they had vaginal sexual exposure to a baseline or new sexual partner during follow-up. A second subset analysis was conducted removing all those who had sexual exposure or were retested before 21 days.

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RESULTS

There were 242 men in the 3 studies who met the criteria for analysis. The reanalyzed rate of retest positive was 12.8% (95% confidence interval, 8.6%–17.0%). There were differences in the rate of sexually exposure during follow-up by study 40.6% (65/160) for study 1, 20.7% (6/29) for study 2, and 30.2% (16/53) for study 3 (P = 0.07). The mean time in days to TOC visit differed by study (45.0; standard deviation, 13 [study 1]; 22.6; standard deviation, 5.0 [study 2]; and 31.6; standard deviation, 12.3 [study 3], P < 0.001).

Of the 242 cases included, 36.0% (n = 87) reported unprotected vaginal intercourse during the follow-up period. There was no difference in retest positivity at TOC between those sexually exposed and not sexually exposed during follow-up (14/87 [16.1%] vs 17/155 [11.0%], P = 0.25). Of the 242 men, 21 (8.7%) were tested before 21 days. Though the retest positivity rate among those retested before 21 days was double that of those retested 21+ days posttreatment, the difference was not statistically significant (5/21 [23.8%] vs 26/221 [11.8%], P = 0.16). Of these 242 participants, 81.8% (n = 198) had symptoms of NGU (eg, dysuria or discharge) at baseline, and there was no difference in TOC+ rates for those who had baseline symptoms compared with those who did not (27/198 [13.6%] vs 4/44 [9.1%], P = 0.41). Retest positive rates by city ranged from 2/24 (8.3%) in Jackson to 6/26 (23.1%) in Birmingham. Using the exclusion criteria for this study, TOC-positive rates were 16/160 (10.0%) for study 1, 3/29 (10.3%) for study 2 and 12/53 (22.6%) for study 3 (P = 0.05, Table 2).

TABLE 2

TABLE 2

In the sensitivity analysis, of the 31 men who retested positive at TOC, 2 had no sexual exposure but were tested before 21 days posttreatment, 11 had sexual exposure but were not tested early, 3 had sexual reexposure and were tested early, and 15 had neither sexual reexposure nor were retested early. When all men with sexual exposure only were reclassified, the retest positive rate was 17/242 (7.0%). When those who were retested before 21 days only were reclassified, the rate was 26/242 (10.7%) and when those who either had sexual exposure during follow-up or retested before 21 days were reclassified, the rate was 15/242 (6.2%). When potential false positives (ie, sexual reexposure and/or early testing) were reclassified as negative, the rates were 7/160 (4.4%) for study 1, 2/29 (6.9%) for study 2, and 6/53 (11.3%) for study 3, (P > 0.07 for all comparisons using Fisher exact test). When all those who were either sexually exposed or tested too early were removed from analysis, the rate was 15/138 (10.9%). When excluding those who were sexually exposed or tested too early from analysis, the rates were 7/95 (7.4%) for study 1, 2/18 (11.1%) for study 2, and 6/26 (24.0%) for study 3. These rates were similar by study when comparing study 1 to 2 and study 2 to 3 but were significantly higher when comparing study 3 to 1 (P < 0.03 using Fisher exact test, Table 3).

TABLE 3

TABLE 3

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DISCUSSION

The reanalyzed pooled crude positive (12.8%) and subset (10.9%) rates were higher than the most recent meta-analysis of randomized trials (6.0%)7 but the sensitivity analysis rate (ie, when potential false positives and potential reinfections were reclassified as negative [6.2%]) was similar to the rate of the meta-analysis. The rate from the sensitivity analysis was also similar to a recent RCT conducted in Los Angeles that removed possible reinfections and retested after 2 weeks and found a rate of 3.2% with a range 0.4% to 7.4%.18 It should be noted, however, that the Los Angeles RCT had a follow-up rate of 54% limiting interpretation of the study.

The reclassified rate of 6.2% (when posttreatment sexual exposure and early NAAT testing was classified as negative) of our study was also similar to a study of adolescent women in Indianapolis with Ct (7.9%). In the Indianapolis study, participants were tested after 21 days posttreatment and treatment failure was comprised of women who either lacked sexual exposure or used condoms for all interval coitus and had a positive NAAT with exactly the same genotype at the follow up visit.19 Our reclassified rates was also similar to a study of men in Seattle who were retested 21 days posttreatment and received expedited partner treatment (7.6%).17

Though the vast majority of male Ct cases respond to 1-g azithromycin, this apparent treatment failure rate could be concern from a public health stand point. A recent study modeling the impact of treatment failure on Ct transmission and screening found that every 1% increase in treatment failure would result in a 0.16% increase in baseline prevalence of Ct in a community.12 Therefore, even low prevalence of treatment failure could result in a large impact at the community level. Furthermore, the World Health Organization recommends choosing sexually transmitted infection therapies with >95% efficacy20; thus, the potential for modestly higher Ct treatment failure rates merit attention.

In crude analyses, there was a wide range of retest positivity by city (8.3%–23.1%). The studies included in this analysis, did not have sufficient power to determine if the geographic differences were statistically significant. Moreover, in vitro antibiotic sensitivity analyses were not performed, so no conclusions can be made about geographic differences.

Antibiotic resistance is a concern with any microorganism. One study conducted in Croatia, a country which has the highest human consumption rate of azithromycin of any country in Europe, found that all of the Ct strains collected were susceptible to both azithromycin and doxycycline even at low concentrations.21 Whether or not this can be extrapolated to the United States is not known. A study of azithromycin resistant Ct using a geographically representative sample of adequate size might provide insight about whether azithromycin resistance in Ct is emerging in the United States but may be difficult to undertake given difficulties in culturing Ct22 and may not have relevance given that in vitro resistance testing has little correlation to clinical treatment failure,23

When the methodologies used in the 3 studies reviewed here were harmonized and potential misclassification as a result of sexual exposure and early TOC was minimized, the studies had similar findings. Because 17 of the 32 TOC+ cases had sexual reexposure and/or were tested early, misclassification error is an important concern when interpreting these studies. And while the sensitivity analyses could have resulted in conservative estimates of the true rate, it is important to evaluate the rate range.

The rate of treatment failure in this reanalysis was between 6.2% and 12.8% among men who have sex with women with Ct-related NGU receiving 1 g azithromycin. Some experts have suggested that multidose azithromycin treatment is now indicated24 for the treatment of NGU, whereas others believe that this recommendation is premature.25 Future studies should be done to elucidate the potential genetic basis of resistance and investigate potential epidemiologic makers for this state. These studies should also consider sexual exposure in a more nuanced manner, eliciting when the exposure occurred and if the partner had already been treated, and also possibly using genotype testing as was done by Batteiger et al19 and Geisler et al.18 Multilocus genotyping of pretreatment and posttreatment specimens may provide more precision to estimates of treatment failure rates compared with ompA genotyping methods.26

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