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Original Study

A Randomized Controlled Trial of Partner Notification Methods for Prevention of Trichomoniasis in Women

Schwebke, Jane R. MD; Desmond, Renee A. PHD

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Sexually Transmitted Diseases: June 2010 - Volume 37 - Issue 6 - p 392-396
doi: 10.1097/OLQ.0b013e3181dd1691
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Trichomoniasis is a common cause of symptomatic vaginal discharge. The infection is associated with adverse outcomes of pregnancy and increased risk for HIV (human immunodeficiency virus) acquisition.1,2 In inner city, sexually transmitted disease (STD) clinics in the United States rates continue to be high despite the fact that trichomoniasis is easily treated with single dose, readily affordable medication. The infection is usually asymptomatic in males, and there is currently no licensed screening test to detect infection in men. Thus, there is heavy reliance on partner referral methods for identifying and treating potentially infected males. The usual approach to partner referral for this infection is to ask the female index partner to inform her partner(s) of the need for treatment but it is estimated that only a minority of men seek such care.3 The purpose of this study was to carry out a randomized trial to compare the effectiveness of the 3 methods of partner notification and treatment for sexual partners of women with vaginal trichomoniasis—patient self-referral of partners (the current practice standard), delivery of curative therapy to partners by patients themselves, or public health style disease intervention carried out by specially trained disease intervention specialists (DIS) locating the partners and delivering the medication in the field. Repeat infection rate with Trichomonas at 1 and 3 months of follow-up among the index women was the measure of effectiveness.

MATERIALS AND METHODS

Women ages 19 and older attending the Jefferson County Department of Health in Birmingham, AL, with a culture or wet prep positive for Trichomonas vaginalis were invited to participate in the study. Exclusion criteria included infection with other STD pathogens requiring Health Department DIS intervention (syphilis or HIV), pregnancy or currently breast feeding, recent (8 hours) ingestion of alcoholic beverages or intent to do so in the 24 hours following treatment, allergy to metronidazole, the presence of a sexual partner in the clinic at the time of enrollment, a history of referral by a partner already treated for trichomoniasis, or a report of more than 4 sexual partners in the preceding 30 days. The study was approved by the Institutional Review Boards of the University of Alabama and the Jefferson County Department of Health.

Women agreeing to participate received directly observed treatment with a 2-g stat dose of metronidazole as well as standardized (scripted) educational messages concerning their infection and the need for treatment of sexual partners as is the standard of care in the clinic. A questionnaire on symptoms, sexual practices, health care seeking behavior, and attitudes regarding partner notification was administered. Subjects were screened for gonorrhea, chlamydia, syphilis, and HIV as part of a complete STD screening. Subjects were randomized to 1 of 3 partner intervention methods—usual care as described earlier [partner referral (PR)]; patient delivered partner therapy (PDPT); or DIS interview and DIS-assisted partner notification and treatment.

Patients randomized to PR were given standard messages on the importance of partner treatment as a means of preventing repeat infection and asked to tell their partners to present to the clinic for evaluation and treatment. If the partner did present to clinic, they were offered participation in the male substudy. If agreeable, a brief questionnaire was administered and urethral and urine specimens were collected for testing for T. vaginalis. All partners regardless of their willingness to participate in the male substudy were treated with a directly observed dose of metronidazole 2 g.

The DIS intervention followed existing confidential interview protocols for DIS follow-up of diseases such as gonorrhea or chlamydia. Women were interviewed concerning recent sexual partners and entered into a verbal contract with DIS to refer their partners into the clinic for treatment. The interview process enumerated sexual partners in the preceding 60 days, descriptions, and locating information for those partners. Partners were contacted by telephone within 1 to 2 days of the woman's enrollment and told specifically which clinic nurse to contact and that they would be eligible for remuneration if they participated in the male substudy. Male partners presenting to the clinic as a result of this interaction were consented for the study and treated with metronidazole 2-g stat dose. In addition, urethral and urine specimens were obtained for testing for T. vaginalis and a brief questionnaire administered. If treatment of the male partner(s) could not be verified after 2 working days, DIS attempted to notify exposed partners by telephone or field visits of the need for treatment. For partners who were unwilling to come to the Jefferson County Department of Health STD Clinic for evaluation, interaction with the patient in the field consisted of educational messages, delivery of medication, and if they elected to participate in the male substudy, completion of a short questionnaire regarding the subject's perceptions of the partner notification process, and collection of a urine specimen to be used for diagnostic testing for T. vaginalis. Subjects were consented for these procedures.

The PDPT therapy intervention consisted of a scripted review of the contraindications to the use of metronidazole, including known allergy and use with alcohol, and reinforcement of appropriate dosing or administration, that is, take all pills at once. The subject was provided with metronidazole for up to 4 partners in the past 30 days. The medication was provided in separate vials with easy to read labels restating contraindications and providing a 24-hour phone number by which the partner(s) could contact one of the study team members to address questions regarding the medication, indications for therapy, or further evaluation of symptoms. Thus, male partners of women randomized to PDPT were not available for further study.

Index women were asked to return to the clinic 5 to 9 days after enrollment and treatment for a “test of cure” evaluation to assure the success of treatment. At this visit, specimens were collected using the patient-self collection approach for culture. An interval history of symptom (if present) resolution, treatment side effects, and interval sexual exposure was obtained. Follow-up visits to detect repeat infection were held at 1 and 3 months after the test of cure visit. At these visits an examination was performed, including culture for T. vaginalis, and follow-up questionnaires administered.

Microbiologic Methods for Identifying T. vaginalis

Infection with T. vaginalis was defined as either a vaginal wet preparation positive for motile trichomonads or a positive culture. Trichomonas cultures were performed using the In Pouch TV test (BioMed Diagnostics Inc, White City, OR). Pouches were inoculated with vaginal, urethral, or urine sediment specimens and incubated at 37°C. They were examined microscopically daily for up to 5 days for the presence of motile trichomonads.

Statistical Analysis

An intent-to-treat analysis was conducted on all women who were randomized and received either of one of the study interventions and had a least one follow-up after the test of cure visit. The PR group that consisted of usual care was considered the reference group. The proportion of women who exhibit repeat infection was calculated across the 3 groups with pairwise comparisons (DIS vs. PR, PR vs. PDPT) using the chi-square test or Fisher exact test, and 95% confidence intervals were computed. Descriptive characteristics across the 3 groups were compared by the chi-square test (for proportions) or Fisher exact test or ANOVA for continuous variables.

RESULTS

A total of 484 women were randomized between February 2003 and June 2008 (160 partner referral, 162 partner delivered and 162 DIS arm). The participants had a median age of 27.0 years (mean, 28.8; SD, 8.0) and 94.8% were black. Almost three-fourths of the sample (72.9%) reported having only 1 partner over the past 3 months, with most of these partners being described as regular (67.2%). Over one-fourth of participants (27.1%) reported having 2 or more partners over the past 3 months. Only 7.0% of women in this category had 3 or more partners, with the upper limit being 5 partners. As shown in Table 1, there were no differences across the 3 randomized treatment groups in the baseline characteristics. The majorities of the women reported no condom usage over the last 2 months with the most recent male partner and were black. Overall, 194 of 484 (40.1%) women completed the entire study. The major reasons for study termination were loss to follow-up (34%), persistence or recurrence of Trichomonas (11%), and use of metronidazole for treatment of symptomatic bacterial vaginosis (8%). There were no significant differences in reasons for study termination between groups, including rates of trichomoniasis at the 5- to 9-day visit. Among the 402 women who returned for the 5- to 9-day visit, 19 of 402 (4.7%) were positive for Trichomonas. Although this visit was considered a test-of-cure visit, it is impossible to know if these cases represented treatment failure or repeat infection. The proportion of women reporting vaginal sex since the prior visit was 35.8%.

T1-11
TABLE 1:
Baseline Characteristics of the Female Study Population

Rates of repeat infection in the women at 1 and 3 months of follow-up compared with the reference group of PR are shown in Table 2. At the 1-month follow-up visit there were data on 296 individuals. The difference between the DIS group and the PR (reference) group was not significant [risk ratio (RR) = 1.24, 95% confidence interval (CI): 0.88, 1.74], and the difference between the PDPT group and the PR group was also not significant (RR = 0.74, 95% CI: 0.39, 1.39) However, if the DIS group is compared with the PDPT group, the DIS group had significantly higher repeat infection rates (RR = 1.54, 95% CI: 1.13, 2.10, P = 0.03). For the combination of PR/DIS versus PD there was also a trend toward higher repeat infection rates in the former (RR = 1.27, 95% CI: 1.04, 1.55, P = 0.065). Overall, the proportion of women reporting vaginal sex since the prior visit was 79.1%. There was no significant difference in reported condom usage rates between the 3 groups with approximately half of women reporting condom usage.

T2-11
TABLE 2:
Trichomonas Reinfection at 1 Month and 3 Months Comparing Intervention Arms to Reference Group of Partner Referral Group

At the 3-month follow-up visit there were data on 194 women (40.0% of the randomized population). The difference between the DIS group and the PR group was not significant (RR = 1.23, 95% CI: 0.70, 2.16), and the difference between the PDPT group and the PR group was not significant (RR = 1.50, 95% CI: 1.06, 2.12). At 3 months, the differences between DIS and PDPT and PR/DIS and PDPT were also no longer significant. The repeat infection incidence rate for 3 months was 7.0% (95% CI: 5.0%, 9.0%). Since the prior visit 87.1% of women reported vaginal sex. Reported condom usage between the 1- and 3-month follow-up visits was not significantly different in the PDPT group than as reported between enrollment and 1-month visit. Among all groups, condom usage reported at the 1-month visit was about 50% compared to about 40% at the 3-month follow-up. In addition, there was no significant difference in the number of new sex partners reported with 19% of women reporting a new partner at the 1-month visit compared to 13% at the 3-month visit.

Of the 402 women who returned for the 5- to 9-day visit, a total of 519 male partners were reported. Women in the PDPT arm reported 179 total partners. When asked if they delivered the therapy to their partners the women responded in the affirmative for 143 (79.9%) of the partners. For these 143 partners, the women reported that it was either very or somewhat likely the partners took the medication for 128 (89.5%) of the men. Seven women thought it unlikely that the men took the medication and 8 stated they did not know. Among the PDPT males, 9 were known to have had some problem with the medication by report of the female. All of these were reported as mild nausea/gastrointestinal upset.

The total number of male partners actually enrolled into the male portion of the research study was 115. Forty-five were part of the PR group and the remaining 70 were assigned to the DIS intervention. This represented 25.1% and 43.5% of partners named by the women in these groups, respectively. Among the DIS Group 67 of 70 (95.7%) presented to the clinic as a result of the partner's referral and only 3 were contacted in the field. Thus, the majority of this group could be considered the same as the PR group. If these 2 groups are combined, 33.8% of the male partners presented for treatment. The mean time elapsed from the initial female visit to known treatment dates for males was 7.25 days for the DIS group and 5.0 days for the PR group (P = 0.19). For women assigned to the DIS group, research staff was able to verify treatment for 91 of 161 (56.5%), although 21 refused to participate in the formal study. In the PDPT group, women confirmed verbally that medication was delivered to 143 of 179 (79.9%) of male partners, significantly higher than treatment verification in the other groups (P < 0.001). When women in the PDPT group were queried regarding how likely it was that their partners took the delivered medication, 128 of 143 (89.5%) answered that it was likely. Thus, it seems highly probable that the majority of male partners of women assigned to PDPT were treated for Trichomonas. The disposition of partners is shown in Figure 1.

F1-11
Figure 1.:
Treatment outcomes of male partners by intervention arm.

DISCUSSION

Despite being easily treated with single dose inexpensive medication, trichomoniasis remains highly prevalent in the United States and worldwide. The continued high rates of this infection are a reflection of the lack of a dedicated public health disease control program. Most notably, lack of a diagnostic test for men, asymptomatic infection in men, and failure of partner referral to result in treatment of the male partner are important contributors to ongoing infections.

Lack of resources prohibits active partner identification by local health departments as is performed in the case of syphilis and HIV. Traditional partner referral has been shown to occur in only about 40% of patients with gonorrhea or chlamydia.4,5 Because most men with Trichomonas are asymptomatic,6 it is possible that significantly less than 40% of male partners seek care as a result of partner referral for this infection. Thus, alternative approaches are needed. Partner delivered therapy has been quietly advocated for many years but is not widely instituted due to medicolegal concerns. More recently this approach has gained renewed attention as a method to help decrease rates of gonorrhea, chlamydia, and trichomoniasis.3,7–10 Among a group of women studied in South Africa, partner delivered therapy was chosen as the method of partner notification by the overwhelming majority of women with STD, and these women reported that 94% of the partners took the medication.11 An observational cohort study designed to measure the acceptability of PDPT among women found a significant reduction in incident chlamydia infections in the PDPT group compared to women in the PR group.8 A randomized study of PDPT versus PR in heterosexual men and women with gonorrhea or chlamydia found a significant decrease in new gonococcal infections among those in the PDPT group compared with PR, but there was no statistically significant difference for chlamydia.10 However, a multicenter randomized study of women with chlamydia found no benefit in providing women with medication to deliver to their partner(s).9

Only one other study has addressed the issue of PDPT for women with Trichomonas. The women (463) were randomized to PR versus PDPT and retested for Trichomonas at 1 month. There were no differences in recurrence rates between the groups. Repeat infection rates at 1 month ranged between 6.3% and 9.4%.3 Our study also failed to show a significant difference in repeat infection rates when the 2 intervention arms were compared to PR, usual care. However, at 1-month follow-up PDPT resulted in fewer repeat infections than the DIS or PR/DIS interventions combined. However, there were no adverse events reported from the males in the PDPT group suggesting that this is an acceptable and safe approach. Eighty percent of the women randomized to the PDPT arm reported delivering the medication to their partners and believed that it was likely that 89% of these men took the medication. Treatment could be verified for only 25.1% and 56.5% of men in the PR and DIS arms, respectively. The relatively high percentage of men treated as a result of the DIS intervention was likely because of telephone contact with study personnel informing them of the specific nurse to contact at the clinic as well as the potential to be remunerated for joining the study. Thus, the 25% seen in the PR arm more accurately reflects real-world experience with partner referral for this infection.

Our study contributes important data on cure rates with single dose metronidazole and repeat infection rates. To our knowledge, this is the only large study with a “test-of-cure” visit (within 9 days of treatment). Our data, which showed a cure rate of 95%, confirms that a 2-g single dose of metronidazole is highly efficacious.12–17 In terms of repeat infection rates, our rates were slightly lower than reported in the literature. Soper et al, in a study of the female condom, found that noncompliant users had a recurrence rate of 14%.18 In a study of adolescent girls, the recurrence rate at 3 months was 23.2%.17

An important limitation of our study included a lower than expected repeat infection rate. The original power calculations assumed that the reacquisition rate to T. vaginalis in study participants would be 15% over a 30-day follow-up period, and that the interventions would reduce the infection rates to 7.5% at 1 month. We planned to recruit about 330 subjects per treatment arm (not accounting for losses) to detect significant treatment differences, however, after 4 years of recruitment we were only able to recruit about 50% of this target, mainly due to a less than anticipated number of referrals from the STD Clinic.

In summary, there was no significant difference found in repeat infection rates of Trichomonas for women randomized to interventions differing from the usual care of partner referral when these interventions were compared to PR. There was, however, a lower repeat infection rate among the PDPT group when the DIS or PR/DIS groups were compared directly to PDPT. Partner delivered therapy was not associated with any known serious adverse events and had a high level of acceptance and adherence with delivery of medication to the male partners per self-report of the female index patient. Cure rates with the standard 2-g stat dose of metronidazole were 95% and the repeat infection incidence rate for a 3-month period was 7.0%. Partner delivered therapy can be considered as an option for treating male partners of women with Trichomonas.

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