Doxycycline and Azithromycin for Prevention of Chlamydial Persistence or Recurrence One Month After Treatment in Women

A Use-Effectiveness Study in Public Health Settings

Abstract

Background: 

To treat chlamydial infection, the Centers for Disease Control and Prevention recommends either a single dose of azithromycin or a 7-day course of doxycycline. Cost is a concern with the single-dose regimen; compliance is a concern with the multidose regimen.

Goal: 

To compare the use-effectiveness of azithromycin and doxycycline for preventing persistence or recurrence ofChlamydia trachomatisinfection in women and to evaluate associated risk behaviors.

Study Design: 

One hundred and ninety-six chlamydia-infected women and their sex partners were recruited into a randomized controlled trial of single-dose versus multidose regimens in seven public health clinics, with no incentives for enrollment, compliance, or follow-up. The outcome measure was a positive test forC. trachomatisby polymerase chain reaction testing at 1 month after treatment.

Results: 

C. trachomatispositivity at 1 month was similar for women receiving single-dose (5.1%, 5/98) and multidose therapy (4.1%, 4/98). Reported compliance among 73 women taking multidose therapy was 94.5%. A twofold to threefold increased risk of chlamydial persistence or recurrence was observed among women who were ≤24 and white or who reported: a recent new partner, multiple partners, or a partner who may have had multiple partners at the time of enrollment or that not all partners were treated during the 1-month follow-up period after initiation of treatment.

Conclusions: 

The use-effectiveness of single-dose and multidose therapy was comparably high. Observed rates of persistence or recurrence were consistent with reported rates of pharmacological treatment failure. However, all women withC. trachomatisdetected at 1 month had behavioral risk factors that may have contributed to reinfection.

IN THE UNITED States, genital Chlamydia trachomatis infections are the most commonly reported infectious disease.¹ Worldwide, an estimated 7.2 million years of healthy life were lost in 1990 alone as a consequence of genital chlamydial infections and their complications.² These complications, which are serious and frequent, include pelvic inflammatory disease, infertility, ectopic pregnancy, chronic pelvic pain that frequently requires surgery, an increased risk of prematurity in infants born to C. trachomatis-infected women, conjunctivitis and pneumonia in newborns, and a threefold to fivefold increased risk of human immunodeficiency virus (HIV) acquisition.^3–8 Evidence from animal studies suggests that many of the sequelae associated with chlamydial infection are related more to recurrent or persistent infection than to the initial infection.^3,9,10

Treatment of C. trachomatis infection is simple and efficacious. Recommended treatments for uncomplicated cervical chlamydial infections published by the Centers for Disease Control and Prevention (CDC) in the 1993 Sexually Transmitted Diseases (STD) Treatment Guidelines included a 7-day course of doxycycline, or a one-time dose of azithromycin.¹¹ Although single-dose therapy costs four to twelve times as much as multidose therapy, compliance is a concern with multidose regimens. Therefore, both public and private prevention programs face important trade-offs regarding the different regimen's use-effectiveness, which is a function of both efficacy and compliance.¹² Our study was designed to evaluate whether rates of persistent or recurrent chlamydial infection differed in women who, along with their male partners, received single-dose therapy, compared with women who, along with their male partners, received multidose therapy. Additionally, we evaluated the association between a number of sexual behaviors and chlamydial persistence or recurrence.

Methods

Setting and Study Population

The seven participating clinics provided STD (n = 4), family planning (n = 2), or primary care (n = 1) services and were located in New York City (NYC); Buffalo, NY; Chautauqua County, NY; and Tampa, FL. The study was approved by the Institutional Review Board (IRB) of the Centers for Disease Control and Prevention (CDC) and the State of Florida Department of Health & Rehabilitative Services Review Council for Human Subjects.

Women who were 16 years of age or older, not pregnant, and not taking antibiotics at baseline were eligible for enrollment. These women were enrolled either (1) presumptively at the time of treatment initiation, but before test results for C. trachomatis were known, or (2) in the case of asymptomatic women, on the basis of a positive test result during routine screening. Criteria for presumptive enrollment included having either mucopurulent cervicitis or a male partner with nongonococcal urethritis. Those presumptively enrolled women whose C. trachomatis test results later proved negative were omitted from the study and did not participate in further follow-up. Thus, our study included only those women with laboratory-confirmed C. trachomatis infection. In addition, if symptomatic men had more than one female contact who tested positive, only the first woman identified as positive was enrolled.

Enrollment and Allocation to Treatment

All women who attended participating clinics and met study inclusion criteria were tested for C. trachomatis and were invited to participate in this study if their test result was positive. Once a woman was enrolled, we attempted to locate and enroll her male partner(s). However, a woman was not excluded if her male partner(s) could not be located or subsequently refused to participate. Alternately, when a man presented to a participating clinic with nongonococcal urethritis, we attempted to locate and test his female partner(s). These female partners were subsequently enrolled if their test results were positive. For the purposes of this study, specially trained STD program field staff participated in locating sex partners in accordance with standard protocols. After providing informed consent, both the woman and her male partner(s) were randomized as a unit to receive either multidose (100 mg of doxycycline twice daily for 7 days) or single-dose therapy (1 gram of azithromycin), the latter being directly observed. All located male partners were examined and treated in the clinic. All medications were stored in small bottles inside of opaque, sequentially numbered, sealed envelopes. Thus, clinicians were unaware of the treatment arm to which patients had been allocated until after therapy was dispensed. All participants receiving both multidose and single-dose therapy were instructed to refrain from resuming sexual activity until 1 week after initiating treatment. This advice, which is consistent with that promoted in conventional STD counseling recommendations, has as its basis the need to refrain from sexual activity until all patients and their partners are treated.^13,14

Data Collection

The principal predictor of interest for this study was type of therapy (single- or multidose) dispensed to infected women and their male partners. At enrollment, trained interviewers used standardized questionnaires to measure other risk factors for chlamydial persistence or recurrence, including age, race, marital status, gender, more than one sex partner in the past 2 months, new sex partner within the past 2 months, partner who may have had multiple partners within the past 2 months (woman answers either "yes" or "not sure" to the question regarding whether partner has other partners), consistent use of condoms (defined as "every time"), and use of oral contraceptives. Additional potential risk factors measured at the 1-month follow-up visit included reported compliance with multidose therapy, number of partners receiving treatment, consistent use of condoms since diagnosis, new partner acquisition, and early resumption of sexual activity. Limited data were available regarding this last risk factor because of late addition to the questionnaire. Data obtained from male partners of infected women included reported compliance and interim sexual behaviors during the month after treatment for their initial infection. Based on findings from Cerin et al,¹⁵ compliance with the doxycycline regimen was defined as taking the medication for 5 or more days.

Laboratory Testing

Both initial and follow-up testing were conducted. To identify women eligible to participate in the study, the Erie County Laboratory, Chautauqua County Laboratory, the New York City Bureau of Laboratories, and the Office of Laboratory Services in Tampa, FL, tested endocervical specimens for C. trachomatis using either a direct fluorescent antibody test (DFA), enzyme immunoabsorbent assay (EIA), or DNA probe test (Gen-Probe PACE-2). Universal screening of women was performed at all STD and primary care clinics and at family planning clinics in Florida, whereas women attending the family planning clinic site in New York were screened based on the presence of behavioral risk factors, signs, or symptoms. C. trachomatis test results were also available for male partners receiving care at all sites except the two clinics located in New York City.

A commercial polymerase chain reaction (PCR) assay for C. trachomatis (Amplicor PCR; Roche Molecular Systems, Branchburg, NJ) was used to perform follow-up testing of women at 4 weeks after initial testing using both endocervical and urine specimens. If either specimen was positive, we categorized the woman as having persistent or recurrent C. trachomatis infection. Evidence from previous reports suggests that by 4 weeks after initiation of treatment, DNA amplification tests are unlikely to detect nonviable organisms.¹⁶

Data Analysis

The study coordinator at each participating site reviewed all questionnaires within 24 hours of completion for errors and omissions. Interviewers contacted study participants to supply missing data. All data were entered centrally, with double-entry, and analyzed using SAS software. Data analyses were performed to identify errors, outliers, ranges, frequencies, and means of all independent and dependent variables. Univariate analyses were used to generate unadjusted relative risks and 95% confidence intervals for testing of hypotheses. Multivariate modeling was not used to generate adjusted effect estimates since the randomization was effective in eliminating differences between the two groups in the distribution of known potential confounders. Given the sample size, our study had greater than 80% power to detect a difference of 15% or more at the 95% confidence level in treatment failure rates between azithromycin and doxycycline, assuming a 5% treatment failure rate with azithromycin. This magnitude of difference is consistent with assumptions used in models comparing the cost-effectiveness of azithromycin with that of doxycycline.^17,18

Results

Nine hundred and forty-three women were eligible for enrollment on the basis of either symptoms, contact to a male partner with urethritis, or a positive routine screening test. Four hundred fifty- one were eliminated owing to either direct refusal by the women (n = 77) or refusal by the male symptomatic partner who presented to the clinic before examination of the woman (n = 374). Thus, from this patient pool, 492 women were enrolled with informed consent either presumptively (i.e., as the index woman or partner of a symptomatic man) or based on a positive screening test. A total of 261 test- positive women were identified from this group. Follow-up specimens for PCR testing at 1 month were obtained for 196 (75%) of these C. trachomatis-positive women. Among women who completed follow-up testing, the majority received care in either STD (n = 127) or family planning clinics (n = 63); the remaining six received care in publicly funded primary care clinics. Follow-up questionnaires were available for 165 (84%) of the 196 women for whom treatment assignment and follow-up test results were known; baseline and follow-up questionnaire data were not available for 17 single-dose group and 14 multidose group women owing to unforeseen administrative difficulties.

The distribution of demographic and baseline behavioral characteristics that may have influenced the likelihood of early persistence or recurrence of chlamydial infection were compared between those who received single-dose versus multidose therapy (Table 1). Both women receiving single-dose and those receiving multidose therapy were similar with respect to age, race, and behavioral characteristics. Overall, the majority of our study population were less than 25 years of age (73%) and African-American (57%). The demographic characteristics for those women who refused participation were similar (<25 years: 77%; African-American: 78%).

TABLE 1: Characteristics and Clinical Outcome of Participating Women by Type of Therapy

The incidence of persistence or recurrence of chlamydial infection at 1 month in women receiving single-dose therapy (5.1%, 5/98) and those receiving multidose (4.1%, 4/98) therapy did not differ (relative risk [RR] 1.2, 95% confidence interval [CI] 0.35–4.5, Table 1). We considered a variety of behaviors during the 1-month follow-up period that may have influenced the effectiveness of treatment. For 73 women taking multidose therapy who reported the number of days on which the multidose regimen was taken (range 0 to 7 days), 69 (94.5%) reported taking doxycycline for 5 or more days (7 days = 67; 5 days = 2); data were not available for 25 women (Table 1). For the 52 male partners taking multidose therapy for whom data were available, 100% reported taking doxycycline for 5 or more days (7 days = 51; 6 days = 1). Data from a limited number of participants indicated that women receiving single-dose therapy were more likely to report resuming sexual activity less than 1 week after initiating treatment than those receiving multidose therapy (single-dose: 36%, multidose: 22%; RR: 1.6, 95% CI 0.75 to 3.6) (Table 1). A similar finding was observed among a very small group of male partners with data available, demonstrating a significantly increased probability of early resumption of sexual activity (single-dose: 47% of 17; multidose: 17% of 24; RR: 2.8, 95% CI: 1.01 to 7.9). Behaviors such as inconsistent condom use after diagnosis, partner treatment status, and new partner acquisition after treatment were not associated with treatment type (data not shown).

Since the risk of persistence or recurrence of infection in women was not influenced by type of therapy dispensed, the relationship of demographic characteristics, as well as behavioral risk factors reported at enrollment and at the 1-month follow-up visit were evaluated for the combined study population (Table 2). Although no risk factors attained statistical significance, approximately a twofold to threefold increased risk of persistence or recurrence of infection was observed among women <25 years of age, of white race, and among those who, at enrollment, reported multiple partners, a recent new partner, or a partner with multiple partners, and among those who, at follow-up, reported that not all partners had been treated.

TABLE 2: Relative Risks of Persistent/Recurrent C. trachomatis Among Women According to Demographic and Behavioral Characteristics

Review of the characteristics of the nine women who were persistently or recurrently infected at 1 month showed that almost all (8/9) were 24 years of age or younger, all reported compliance, and all reported at least one behavioral risk factor that would increase the risk of chlamydial recurrence. Furthermore, each woman infected at follow-up had at least one of the following two characteristics: (1) their partner may have had multiple partners (7/9) or (2) not all their partners were treated (6/9) (Table 3).

TABLE 3: Characteristics of Nine Women Positive for C. trachomatis Infection 1 Month After Treatment

Discussion

We found that the use-effectiveness of single-dose and multidose therapy for the prevention of persistence or recurrence of chlamydial infection 1 month after initiation of treatment in women was similarly high. Approximately 95% of infected women had negative laboratory tests 1 month after diagnosis. Furthermore, reported compliance with multidose therapy was also approximately 95%.

Several randomized trials have demonstrated that, under the conditions of investigative rigor that characterize efficacy studies, the bacteriologic efficacy of azithromycin equals that of doxycycline for both women and men.^19–22 However, our study posed a different question: Is the useeffectiveness of single-dose therapy superior to that of multidose therapy, under the conditions of typical compliance and in clinic sites that are not affiliated with university research centers. Findings from the only other published report comparing the use effectiveness of single-dose and multidose therapy are consistent with our own and demonstrate that the use-effectiveness of azithromycin is approximately equal, but not superior to, that of doxycycline when compliance rates for the latter are high.²³

However, in contrast, reports that have used modeling to compare the cost-effectiveness of single-dose and multidose therapy for the treatment of uncomplicated chlamydial infections in women have uniformly assumed that the use-effectiveness of azithromycin would be superior to that of doxycycline.^17,18 These reports, which include an economic evaluation conducted by one of our coauthors (S.D.H.), were published before any use-effectiveness studies had been completed. In addition, they were based on assumptions from the compliance literature that (1) noncompliance with multidose therapy is in the 20%-50% range and (2) noncompliance constitutes treatment failure.^24,25 One report that evaluated the effect of duration of multidose therapy on treatment failure for C. trachomatis demonstrated greater than 80% cure rates for women who took only 4 days of doxycycline.¹⁴ This finding suggests that the effect of non-compliance, if defined as not having taken 7 full days of doxycycline, may have been overestimated in the economic models. In addition, our study indicates that, at least among women willing to volunteer for participation, the compliance rates in public health settings may be higher than previously assumed. Among women in our study population for whom compliance was known, approximately 95% reported taking at least 5 days of therapy. Although self-reported compliance may be exaggerated, the high cure rates are consistent with fairly high levels of actual compliance. In addition, although compliance data were not available for 25 women, the observed failure rate for doxycycline was consistent with expected pharmacological failure rates and therefore with a level expected in a highly compliant population.

Although elevated risks of persistent or recurrent chlamydial infection were not related to type of therapy in our study, certain demographic and behavioral characteristics appeared to be associated with the microbiologic outcome for the combined study population. Women who were less than 25 years of age and white demonstrated an increased risk of chlamydial persistence or recurrence. A twofold to threefold increased risk was also observed among women who reported either multiple partners, a partner with multiple partners or a recent new partner at the time of enrollment, or during the follow-up period, not all partners treated. In addition, all nine persistently or recurrently infected women in our study were characterized as having either at least one untreated partner or a partner with multiple partners and therefore a direct or indirect source of reinfection at the 1-month follow-up evaluation.

Contrary to advice delivered by clinic staff, both infected women and a small group of their male partners who received single-dose therapy were twice as likely as those receiving multidose therapy to resume sexual activity during the first week after receiving therapy. Although this behavior may increase early reexposure to potentially infectious partners, it does not lead inevitably to reinfection, as evident by the comparably low rate of persistent/recurrent infection observed in the single-dose group. Pharmacokinetic studies demonstrate that following a single 1.0-g dose, azythromycin levels remained above the minimal inhibitory concentrations for C. trachomatis in cervical tissue and mucous for at least 7 days.^26,27 Similarly, doxycycline remains at therapeutic levels during the 7 days of treatment, provided it is taken as instructed.²⁸ What appears to be more relevant than early resumption of sexual activity is the need to prevent reexposure when antibiotic levels have declined by ensuring adequate treatment of all sex partners.

We considered potential limitations that may have influenced our results. It is unlikely that our findings were biased by selective attrition because loss to follow-up did not differ among women receiving single-dose, compared with multi-dose, therapy. However, because of small clinic-specific sample sizes and differences in loss to follow-up among participating clinics, we were unable to evaluate the influence of potential differences in persistent or recurrent chlamydial infection by clinic type (family planning, STD, primary care). Higher location and follow-up rates for male partners of infected women would have improved our study by allowing us to consider the influence of infection status of male partners on persistence or recurrence in women. Finally, and most importantly, all randomized trials, by nature, are studies of volunteers because only those who consent to participate in the study can be enrolled. Although the demographic characteristics of those women who refused are generally similar to those who agreed to participate in this study, the possibility that compliance may be correlated with participation suggests that these findings cannot be generalized beyond the types of patients who would have been eligible for and willing to participate in this study.

Because C. trachomatis infections are the most common bacterial STD, costs of prevention and control are substantial, although potential savings of averted complications are much greater.²⁹ The marked cost differential between single-dose and multidose therapy makes choice of preferred therapy a much more central issue in the current environment of managed care and reduced funding of public facilities. All of the four bacteriologic efficacy studies and the two use-effectiveness studies (including the present report) are consistent in showing similarly high cure rates for single and multidose therapy.^19–22) Thus, in clinical settings where the compliance rate with a 7-day regimen is likely to be high, doxycycline remains a highly effective, inexpensive regimen. However, clearly, there are also many individuals for whom a single-dose regimen, even if more expensive, would be preferred. Single-dose therapy should therefore be available in formularies of all health care institutions that provide care to persons who may have chlamydial infections to provide treatment for individuals for whom compliance may be in question.

Our data also suggest that other risk factors, especially those relating to failure to treat all sexual contacts, including partners of partners, may play as important a role in persistence or recurrence of infection as does pharmacological treatment failure. Thus, the notification, referral, and treatment of all contacts that exist within an infected individual's social network appear to be an essential component of the prevention of persistent or recurrent infection.