Kissinger, Patricia PhD*; Schmidt, Norine MPH*; Mohammed, Hamish PhD*; Leichliter, Jami S. PhD†; Gift, Thomas L. PhD†; Meadors, Bernadette MD‡; Sanders, Cheryl MSN*; Farley, Thomas A. MD, MPH*
Trichomonas vaginalis (TV) is a sexually transmitted infection (STI) that has been associated with significant morbidity, especially in pregnant women.1 TV infection has also been found to be associated with increased susceptibility to human immunodeficiency virus (HIV)-1 and increased likelihood of HIV vaginal shedding among HIV-infected women.2,3 In the general population, prevalence has been reported between 5% and 13%.4 Much higher rates have been observed in select populations, such as commercial sex workers, STI clinic patients, and HIV-positive women.2,5–7 Recurrence rates as high as 29% have been documented.2,4 Because recurrence is thought to represent reinfection from sex partners, one factor that should influence the high recurrence rates is lack of partner treatment.
The preferred medical management for sex partners of persons with any STI is for all partners to visit a health care clinic for diagnostic testing, treatment, and counseling. However, notifying partners and persuading them to come to a clinic is often difficult. Referral of partners by the index patients, or partner referral (PR), is the method most often used by health care providers to prompt the partners to seek care.8 Index patients are asked to inform their partner(s) that they have been exposed to an STI and encourage them to go to a clinic for testing and treatment. Unfortunately, when providers rely on PR, many partners do not get treated. Patients do not always notify their partners,9–11 and when they do, their partners may not seek treatment. Studies of chlamydia, gonorrhea, trichomonas, and urethritis infections among women demonstrated that only 29% to 59% of named male partners actually sought care at a clinic and were treated.11–17 There are several reasons partners remain untreated, including a lack of notification by the index patient, the partners’ unwillingness or inability to seek medical evaluation, and failure of providers to appropriately manage partners. Patient-delivered partner treatment (PDPT) has the potential to break down several of these barriers to partner treatment.
PDPT is the process whereby antimicrobial treatment for partners is provided to an index patient, who is then instructed to deliver the medicine to partners, along with standard instructions to seek evaluation similar to PR. The efficacy of PDPT for chlamydial or gonorrheal infections has been examined in both retrospective studies18,19 and randomized controlled trials10,20–22 and has shown to increase the number of partners who are treated and reduce recurrence rates, especially for heterosexuals with gonorrhea.
The goal of the current study was to examine the efficacy of PDPT for women with TV infections compared to standard PR about increased numbers of partners treated and decreased recurrence. To develop additional options for partner treatment, a second comparison group, booklet-enhanced partner referral (BEPR), was included. BEPR was developed from pilot work in a rural Louisiana public health clinic that suggested that the numbers of partners that came in for services increased substantially when the index patients were given a booklet with tear-out cards for their partner(s) (personal communication, Louisiana Office of Public Health). It was believed that the booklets facilitated communication between partners, which may be an important barrier to partner treatment.
Women who attended the Orleans Women’s Health Clinic in New Orleans between December 2001 and August 2004 were offered enrollment in the study if they had (1) a culture-confirmed diagnosis of TV, (2) were not in their first trimester of pregnancy, (3) had no medical contraindication to taking metronidazole or bringing metronidazole to a partner, and (4) had at least 1 male sex partner in the last 60 days.
The diagnosis of TV was made using the InPouch culture system. InPouch specimens were read within 15 minutes of collection and then 2 more times in a 5-day period. Specimens were incubated at 37°C in the interim. Women were treated at baseline using either 2-g single-dose or a 7-day, 500-mg, twice-per-day regimen for women who also had bacterial vaginosis. Metronidazole treatment was directly observed by the clinic nurse for those on the single dose, and the first dose was observed for those on the 7-day regimen.
For partner treatment, index women were randomized to one of 3 study arms.
Women were instructed to tell their partners that they needed to go to a clinic for STI evaluation and treatment.
Women were given a wallet-sized booklet containing 4 tear-out cards with information for the partner and treatment guidelines for the providers that would see the partners. The partners could then present this card at a clinic to help the clinician better treat them. If women had more than 4 partners, they were given additional booklets.
Women were given packages containing 2 g metronidazole for up to 4 identified sex partners. These packages contained written instructions about how to take the medication, warnings about side effects, and a nurse’s pager number to call if there were any questions or if the partner encountered any problems. All medications were distributed in containers with childproof caps, and the partner’s initials and birth date were written on the bottle. This was a requirement of the Louisiana State Pharmacy Board. Names were not documented on the woman’s study or medical records. Although PDPT is explicitly legal in only 4 states,23 in most states it is not explicitly forbidden either, and it is a common practice.8
All 3 partner treatment modalities do require that the women have interaction with her partner in varying degrees. It was hypothesized that BEPR and PDPT were additional tools that the woman could use to facilitate partner notification beyond the standard PR.
Before this study, there was no screening for TV at this clinic, and a diagnosis was usually made via Papanicolaou smear or according to symptoms. Because there was no consistently used clinic protocol for counseling women for TV, study staff counseled women on all arms about TV and the importance of partner treatment using a standard protocol. This was done before randomization, and each counseling session lasted an average of 10 to 20 minutes.
Randomization was performed using previously prepared envelopes and was conducted using a blocked scheme of 3 or 6 units (i.e., women) using Microsoft Excel software. Information about each partner was elicited from the index women at baseline and 1 month using a computer-assisted self-interview (CASI). Questions were modeled after the Infertility Prevention Program multicentered trial21 and were adapted and pilot tested before use. Questions on the CASI included information about sexual behavior, condom use, and treatment for each partner identified.
Patients were asked to return 4 weeks after their initial visit (with a window of 2–8 weeks) for a follow-up interview and a gynecological examination for TV culture. Women who retested positive were retreated with the 7-day dose and asked to return 1 month later. After the second dose, if the woman remained positive, a sample of the vaginal fluids was sent to the Centers for Disease Control and Prevention for metronidazole-resistance testing. If a woman was interviewed over the phone but did not have a pelvic examination, she was given a smaller incentive. Women were asked outcome questions for each partner identified on the baseline survey and were also asked questions of any new partners acquired in the follow-up period. The outcome of interest was the response to this question: “Did [partner name] tell you that he took the medicine?”
Patients received a small monetary reimbursement for their time. All participants received $10 for baseline interviews. For the first 2 years of the study, participants received $20 for returning to the clinic for follow-up and $10 if their follow-up visit was completed in the field. To improve follow-up rates, after the first 2 years, the incentive for undergoing a TV culture was increased to $30. Institutional review board approval was obtained from Tulane University Health Sciences Center, Centers for Disease Control and Prevention, and the Louisiana Office of Public Health.
Study staff collected time-motion data to determine the time required to describe the interventions to the patients. These data were combined with staff wages, rent, and costs of utilities to determine counseling costs. The counselors were disease investigation specialists and a registered nurse who provided specific dispensing information for women in the PDPT arm. Booklet and partner pack costs were also included.24 Literature estimates of the cost of clinic visits for reinfected symptomatic patients (who would be expected to seek care) and for their partners were used.3 Because the only purpose of the baseline interviews and follow-up visits was to gather data for the study, staff time for these and for incentive reimbursements was not included. Costs were calculated from a program perspective, including all health care–associated costs that would be incurred by a local program for TV-associated care for index patients and their partners but excluding costs for potential concurrent STIs, sequelae of TV infection that would not likely be paid by programs, and costs for patient and partner lost wages and travel. For the cost-effectiveness analysis, the number of partners taking the medicine was used as the outcome measure. A decision analysis was used to estimate the costs and outcomes associated with each of the interventions.
Data analysis was conducted using SAS 9.0 (SAS Institute Inc., Cary, NC) and DATA Pro 1.0 (TreeAge Software, Williamstown, MA). For partner-level analyses, bivariate and multivariate analyses were conducted using generalized estimating equations (GEE) to accommodate the intraclass correlation that exists for multiple partners per index woman. For index-level analyses, logistic regression was conducted.
Baseline Index Characteristics
Index women (N = 463) were mostly black (99.1%), had high school education or greater (87.3%), and were less than 24 years of age (52.1%). The mean age was 25.8 (SD 6.8). The majority reported 1 partner in the 60 days before the baseline interview (86.8%). Most of the women reported symptoms (62.9%) including discharge (49.9%), itching (37.4%), and burning (11.2%). Only 4 women reported crack, cocaine, or heroin use in the 2 months before baseline, but 24.5% reported binge drinking. All women were TV positive at baseline (71.2% were detected on the first culture reading and 28.8% were detected on subsequent reading). The majority (98%) were treated with the 2-g single dose of metronidazole; the remaining (n = 10), with the 7-day course. There were 155 women in the PR, 154 in the BEPR, and 154 in the PDPT arms. Women in the 3 arms were similar about race, education, age, report of baseline symptoms, binge drinking, and substance use and number of partners.
Baseline Partner Characteristics
Index women reported on 521 partners at baseline; 82.5% were described as “main” sex partners, 97.6% were male, 8.3% were spouses, and 28% lived with the index patient. Few women reported that their partners gave them money or drugs for sex (1%) or that the partners abused them physically (2.9%). Most women said they could contact the partners if they wished (89.0%).
Characteristics by Report of Partner Taking Medication
Of 463 women enrolled at baseline, 412 (89%) returned for a follow-up visit. Those who returned were similar to those who did not return by race (P = 0.48), age (P = 0.45), education (P = 0.90), and number of partners at baseline (P = 0.15).
Women in the PDPT compared to the BEPR arm were more likely to have seen their partners, have checked to see if they were treated, report that their partners took the medicine, and to have seen their partners take the medicine. When compared to PR, women in the PDPT arm were more likely to have seen their partners take the medicine (Table 1).
In bivariable GEE analysis, women from partnerships where the man was reported to have taken the medicine were similar to women from the partnerships where the man was reported to have not taken the medicine by race, education level, and baseline symptoms. In multivariable GEE analysis, women who reported their partners did take the medicine were more likely to be older, consider that partner to be the main partner, have only 1 partner, and were more likely to have reinitiated sex during follow-up. Women in the PDPT arm were somewhat more likely to report their partners took the medicine (OR, 1.69; 95% 95% CI, 0.92–3.13; P = 0.09) compared to PR, but this was not statistically significant. Women in the BEPR arm were less likely to report their partners took the medicine (OR, 0.52; 95% CI, 0.30–0.90; P = 0.02) compared to PR (Table 2).
Characteristics by Follow-up TV Result
During follow-up, 81.2% were retested for TV. Of those who were retested and completed an interview, 81.7% saw their baseline sex partners, 87.3% talked to these partners about the infection, 82.0% gave their partner the intervention, 43.0% resumed sex, and of these, 57.8% reported using a condom consistently. These factors were similar by arm.
Of 376 women who were tested during follow-up, 8.2% were TV positive, and rates were similar among study arms (PDPT 9.4% versus BEPR 9.0% versus PR 6.3%; P = 0.64). The following characteristics were examined for association with TV positivity at 1 month but were not found to be associated: race, age, symptoms at baseline, binge drinking, number of partners, acquisition of a new sex partner during the follow-up, unprotected sex with partner during follow-up, reexposure to an untreated partner, and intervention arm (Table 3). Therefore, multivariable results were not pursued.
Of the 31 women who retested positive, 30 women reported no reexposure (i.e., they were abstinent or did not report unprotected sex with any partner before they were treated during the follow-up). Of these 30, 26 responded to retreatment with a higher dose of metronidazole. Specimens from the remaining 4 women were submitted to the Centers for Disease Control and Prevention for sensitivity testing. All 4 were reported to have mild resistance to metronidazole.
Staff costs for describing the interventions did not significantly differ across arms (Table 4). Only the staff time for instructing the patient was included in staff costs; costs associated with the preceding clinical examination (which occurred in all 3 arms) were excluded. At baseline partner treatment rates (Table 1), the cost per partner treated for PDPT was lower than that of the other interventions, primarily because we assumed that none of the partners in the PDPT arm received clinical care at baseline. We lacked data on the rate at which partners in the PDPT arm might have sought clinical services (instead of or in addition to taking the medicine if provided by partners). In sensitivity analysis, we varied this rate from 0%–75% and also varied the clinic visit costs (Table 4). Over the entire range of clinic visit costs, unless more than 51%–53% of partners in the PDPT arm sought clinical care, the cost of PDPT (per woman or per partner treated) was lower than BEPR and was lower than the cost of PR over the entire range. We also varied the rate of TV positivity at follow-up in the PDPT arm separately from 5%–20%. PDPT remained less costly than BEPR and PR over the entire range.
In this study, among women with TV, we found that PDPT was not associated with more partners being treated (per the index woman’s report) or a lower recurrence rate compared to the standard PR. Although we did not have sufficient power for an equivalency study, the trends for partners treated and recurrence rates for PDPT and PR were very similar, suggesting that they are equivalent. Several other studies have demonstrated that PDPT was superior compared to PR for reducing recurrence of STIs, but these studies were examined for chlamydial or gonorrheal infections.10,21,22 It is possible that agent and host factors are different for TV. For example, women with TV in general are older than women with CT and GC. The mean age of women enrolled in this study was 25.8 years. It is possible that because the women were older than women enrolled in the other studies, they were more mature in their approach to partner treatment.
In the population of women in this study, there was a high compliance with partner notification among women in the standard of care (i.e., PR) arm. High compliance may be a result of the counseling that was provided to all arms. Women on all arms received an average of 10 to 20 minutes’ worth of counseling about the need to notify their partner. In this study, there were low rates of reinitiation of sex and unprotected sex in all arms. We only followed the women for 1 month. Perhaps longer follow-up would have increased the likelihood of sexual reexposure. Although statistical power could have been an issue, it is unlikely because the trend we found was the opposite of what we expected. We found that the percentage of women who retested positive was higher, though not statistically higher, in the PDPT compared to the PR arm. In sum, it appears that the women on all arms of this study were compliant with the partner treatment intervention and unlikely to have been reexposed.
The cost of the PDPT arm was lower than that of the BEPR or PR arms. This was largely due to the assumption that partners would seek clinical care at a lower rate than those in the other 2 arms. Although PDPT is less costly than treatment dispensed during a clinical examination, there could be other benefits to being seen by a clinician, such as the opportunity to screen for other STDs. An STD clinic chart review found that 10.3% of male partners of TV patients had concurrent chlamydia or gonorrhea.25 If such additional infections were successfully treated, they could convey additional benefits to overall STI and HIV morbidity in the population through reduced disease transmission. A dynamic mathematical analysis could be used to estimate the population-level magnitude of this potential benefit but would require additional data on concurrent STIs and other partners of the male partners of women in this study.
The findings that women in the BEPR arm fared worse than PR for partner treatment was unexpected and is unexplained. In a similarly designed study of men with urethritis, partners of men who were randomized to the BEPR were more likely to report having taken the medicine, and index men were less likely to have recurrent STIs.22 There appear to be large gender differences in the response to this intervention. One randomized clinical trial (RCT) conducted in Africa found that contact slips increased the number of partners treated for men but not for women.26 Another observational study in England showed that infection-specific contact slips improved the percentage of partners treated for both genders.27 Unlike our original notion, we now hypothesize that the booklet made the women more passive and so they did not discuss as much with their partner or were not as aggressive at assuring their partners were treated compared to the other arms. Although we do have some qualitative data supporting this idea, the hypothesis needs to be fully tested, and until then, booklets should probably not be used in this context.
The high percent of women testing positive after treatment (8.2%) was also surprising. This is especially true given the low rates of self-reported reexposure. It is possible that self-report of reexposure was inaccurate. Upon stratified analysis, including women who admitted reinitiating sex with their original partners (n = 135), there still was no difference between PDPT versus BEPR versus PR for retesting positive at 1 month (3.8% versus 9.5% versus 5.0%; P = 0.45). Further stratification of the 57 women who admitted to having unprotected sex with original partners showed that only women in the BEPR arm retested positive (n = 2).
It is also possible that the 2-g dose is insufficient at treating TV. The original study demonstrating a 97% efficacy rate with 2 g of metronidazole was published in 1980,28 and it is possible that the organism has increased resistance since then. Studies have consistently reported metronidazole resistance rates from 2.5%–5%.29,30 A British study reports that nonresponse to metronidazole is increasing.31 More data on the efficacy of the 2 g dose is needed. In this population, the data indicate that most of the women who retested positive had persistent or resistant infections and were not reinfected.
Among women with TV, PDPT did not result in more partners taking the medicine or lower recurrence rates than standard PR but was less costly than the alternative arms. Given the high rates of recurrence of TV and the increased potential for HIV transmission in the presence of this infection, we think that PDPT is an efficient treatment option. Future studies of this approach in a more natural setting where women are offered the choice of their preferred method will be of great value in helping to determine which subgroups of women will most benefit from this approach.
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