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Improvement of Vaginal Health for Kenyan Women at Risk for Acquisition of Human Immunodeficiency Virus Type 1: Results of a Randomized Trial

  1. R. Scott McClelland1,2,6,
  2. Barbra A. Richardson3,
  3. Wisal M. Hassan2,
  4. Vrasha Chohan6,
  5. Ludo Lavreys2,6,
  6. Kishorchandra Mandaliya8,
  7. James Kiarie7,
  8. Walter Jaoko6,
  9. Jeckoniah O. Ndinya-Achola6,
  10. Jared M. Baeten1,
  11. Ann E. Kurth5 and
  12. King K. Holmes1,4
  1. 1 Department of Medicine, Seattle
  2. 2 Department of Epidemiology, Seattle
  3. 3 Department of Biostatistics, Seattle
  4. 4 Department of Global Health, Seattle
  5. 5 Department of School of Nursing, University of Washington, Seattle
  6. 6 Department of Medical Microbiology, Nairobi
  7. 7 Department of Obstetrics and Gynecology, University of Nairobi, Nairobi
  8. 8 Department of Coast Provincial General Hospital, Mombasa, Kenya
  1. Reprints or correspondence: Dr. R. Scott McClelland, International AIDS Research and Training Program, Univ. of Washington, Box 359909, 325 Ninth Ave., Seattle, WA 98104 (mcclell{at}u.washington.edu).

  1. Presented in part: 17th International Society for Sexually Transmitted Disease Research Conference, 31 July–3 August 2007, Seattle, WA (abstract O–102).

 
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Abstract

Background. Vaginal infections are common and have been associated with increased risk for acquisition of human immunodeficiency virus type 1 (HIV-1).

Methods. We conducted a randomized trial of directly observed oral treatment administered monthly to reduce vaginal infections among Kenyan women at risk for HIV-1 acquisition. A trial intervention of 2 g of metronidazole plus 150 mg of fluconazole was compared with metronidazole placebo plus fluconazole placebo. The primary end points were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis vaginalis (hereafter, “trichomoniasis”), and colonization with Lactobacillus organisms.

Results. Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary end points analysis. A median of 12 follow-up visits per subject were recorded in both study arms (P = .8). Compared with control subjects, women receiving the intervention had fewer episodes of BV (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.49–0.63) and more frequent vaginal colonization with any Lactobacillus species (HR, 1.47; 95% CI, 1.19–1.80) and H2O2-producing Lactobacillus species (HR, 1.63; 95% CI, 1.16–2.27). The incidences of vaginal candidiasis (HR, 0.84; 95% CI, 0.67–1.04) and trichomoniasis (HR, 0.55; 95% CI, 0.27–1.12) among treated women were less than those among control subjects, but the differences were not statistically significant.

Conclusions. Periodic presumptive treatment reduced the incidence of BV and promoted colonization with normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing the risk of HIV-1 acquisition.

In Africa, the region most affected by the HIV-1 pandemic, the majority of new human immunodeficiency virus type 1 (HIV-1) infections occur in women [1]. Biological, behavioral, and socioeconomic factors all contribute to HIV-1 risk in women. Abstinence, mutual monogamy, and consistent use of condoms have been widely promoted for prevention of HIV-1 transmission but may be difficult for women to implement in some settings. Additional strategies are needed to reduce women's risk for acquisition of HIV-1.

Disturbances of the normal vaginal flora may contribute substantially to the population-level risk of HIV-1 acquisition [2]. Bacterial vaginosis (BV), vaginal candidiasis, and infection with Trichomonas vaginalis are common in Africa [3], and multiple prospective studies have shown that each is associated with an increased risk for HIV-1 [4]. Additionally, normal vaginal flora, characterized by a predominance of Lactobacillus species, has been associated with reduced HIV-1 risk [5]. Vaginal infections can be challenging to treat successfully, and they frequently recur [6, 7]. Simple, safe, and inexpensive interventions that effectively reduce the rate of vaginal infections and promote colonization with normal vaginal flora could provide important female controlled, non-coitally dependent strategies for reducing HIV-1 risk in African women.

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Participants And Methods

We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of monthly periodic presumptive oral treatment with 2 g of metronidazole plus 150 mg of fluconazole to reduce the incidence of BV, vaginal candidiasis, and T. vaginalis infection and to promote vaginal colonization with Lactobacillus species among women at risk for HIV-1 acquisition.

Participants. Participants were female sex workers from Mombasa, Kenya, followed monthly as part of an open cohort study of risk factors for HIV-1 [8]. Most worked in bars or nightclubs, supplementing their income with transactional sex. Trial inclusion criteria included HIV-1-seronegative status, age of 18–45 years, not being pregnant or not planning to become pregnant in the next year, and no abnormal vaginal discharge or symptoms of vulvovaginal pruritus. Exclusion criteria included a history of intolerance to either study drug, anticipation of travel outside of the Mombasa area, and inability to abstain from alcohol for 48 h after each dose of study drug. HIV-1-seropositive women identified through screening could access free comprehensive care that included antiretroviral therapy. The study was approved by the human subjects research committees at Kenyatta National Hospital (Nairobi, Kenya) and the University of Washington (Seattle, WA). All participants provided written informed consent.

Procedures. At enrollment, standardized questionnaires were completed during a face-to-face interview to collect information on demographic characteristics and medical and sexual histories. A physical examination, including a speculum-assisted pelvic examination, was performed. Vaginal and cervical swab specimens were collected for laboratory diagnosis of genital tract infections. Vaginal fluid pH was measured using a test strip (ColorpHast 4.0–7.0 [EM Reagents]), and vaginal secretions were tested for the release of an amine odor after addition of a drop of 10% potassium hydroxide. Blood was collected for HIV-1 serological testing, and a urine pregnancy test was performed.

Women were randomized to the intervention or control arms, with participants and investigators remaining blinded to the allocation until after completion of all participant involvement. The study product and computer-generated randomization scheme were prepared by the Harborview Medical Center Investigational Drug Services Pharmacy in Seattle. Women were block randomized into groups of 10 to receive either 8 capsules containing 250 mg metronidazole each plus 1 capsule containing 150 mg of fluconazole or 8 metronidazole placebo capsules plus 1 fluconazole placebo capsule. Individual study drug packets were prepared and identified using sequential numbers. Trained study staff in Mombasa used the packets in numerical order. All study drugs were administered orally as directly observed treatment (DOT) in the clinic.

Women were scheduled to return for monthly follow-up visits. At each monthly visit, they underwent a brief interview, physical examination, collection of genital specimens, HIV-1 serological testing, and urine pregnancy testing and received DOT. Participants could complete up to 12 follow-up visits. Women who became pregnant were excluded from further participation. Data on adverse events were sought and recorded at each visit.

Women who reported abnormal vaginal discharge or vulvovaginal itching were treated syndromically with a single, openlabel, 2-g, dose of metronidazole plus 200-mg doses of clotrimazole vaginal suppositories nightly for 3 nights. When this treatment was provided, the study metronidazole/metronidazole placebo was withheld.

Because of the time required to process laboratory specimens, participants were invited to return 1 week after each examination to receive their test results. At enrollment and monthly follow-up visits, sexually transmitted infections (STIs), including gonorrhea, microscopic cervicitis, and trichomoniasis vaginalis (hereafter, “trichomoniasis”), were treated according to World Health Organization and Kenya Ministry of Health guidelines [9]. Treatment included open-label single-dose therapy with 2 g of metronidazole for all diagnosed cases of trichomoniasis. Asymptomatic women with a laboratory diagnosis of BV or vaginal candidiasis were not treated, because there is currently no indication for treatment of these conditions in nonpregnant women without symptoms.

Laboratory analyses. All laboratory assays were performed in Mombasa. Serological testing for HIV-1 was performed using an ELISA (Detect-HIV [BioChem Immuno Systems]), and the HIV-1 status of samples with positive ELISA results was confirmed using a second ELISA (Recombigen [Cambridge Biotech] or Vironostika [bioMèrieux]) [10]. Testing for herpes simplex virus type 2 was also performed with an ELISA (HerpeSelect [Focus Technologies]). Pregnancy testing was performed using a rapid β-human chorionic gonadotropin test (Plasmatec Laboratory Products).

Vaginal secretions were Gram stained and evaluated according to standardized criteria (Nugent criteria [11]), which assign a score of 0–10 on the basis of the presence of Lactobacillus, Gardnerella, Bacteroides, and Mobiluncus morphotypes. Gram stains of vaginal secretions were evaluated by a laboratory technician who had >8 years of experience with this technique and had received a refresher course before study initiation. A vaginal saline wet mount was examined microscopically (original magnification ×40) for the presence of motile T. vaginalis, fungal elements, and clue cells. A drop of 10% potassium hydroxide was added to the slide, which was then examined a second time for the presence of budding yeast or hyphae. Culture for T. vaginalis was performed in Diamond's modified medium.

In our primary end points analysis, we defined BV as a Gram stain score of 7–10 [11]. In secondary analyses, we also defined BV according to clinical criteria, which require the presence of ≥3 of the following 4 clinical signs (Amsel criteria): homogeneous vaginal discharge, vaginal pH >4.5, amine odor, and clue cells [12]. T. vaginalis infection was defined as the presence of motile trichomonads on examination of the wet mount or by a T. vaginalis-positive culture. Vaginal candidiasis was defined by the presence of budding yeast or hyphae on the vaginal wet mount.

Culture for Lactobacillus organisms was performed on Rogosa agar (Difco TM [Becton Dickinson]) [5], and H2O2 production was evaluated by subculture of Lactobacillus isolates on tetramethylbenzadine (TMB) agar that contained horseradish peroxidase [13]. The presence of Lactobacillus species was defined on the basis of colonial morphologic characteristics and Gram stain findings. Isolates were classified as H2O2 producers if blue pigment was detectable by the naked eye after growth of colonies on TMB agar.

Endocervical secretions were Gram stained and examined microscopically (original magnification ×100). The number of polymorphonuclear leukocytes (PMNs) was counted in 3 nonadjacent fields. Cervicitis was defined by the presence of an average cervical count of ≥30 PMNs. Culture for Neisseria gonorrhoeae was performed on modified Thayer-Martin medium.

Sample size and statistical analyses. The primary outcomes in the trial were the incidence of BV, vaginal candidiasis, and T. vaginalis infection and of cultures positive for any Lactobacillus organisms and for H2O2-producing Lactobacillus organisms. Wecalculated that 88 events for each outcome were needed to have 90% power to detect a 2-fold difference in event rates between the 2 study arms, using an α of 0.05, in survival analysis [14]. On the basis of the anticipated number of events from previous rates in the cohort, the trial was designed to enroll 400 women in order to have ≥90% power to detect a 2-fold difference in event rates for all 5 primary outcomes, provided that participants attended an average of 7 follow-up visits.

After the first 2 years of the trial, it was evident that the number of episodes of T. vaginalis infection was substantially lower than expected. Because the number of events would not approach 88 even with enrollment of 400 women, we determined that the available resources would not allow us to enroll enough participants to achieve 90% power for the end point of T. vaginalis infection. These data were provided to the Data Safety and Monitoring Board, which concurred with our assessment that a sample size of 310 would provide ≥90% power to detect 2-fold differences in the other 4 end points. Thus, the final enrollment in the trial was 310 participants.

Characteristics of the women enrolled in the treatment and placebo arms were compared using χ2 tests for bivariate data and Wilcoxon rank sum tests for continuous data. Losses to follow-up were compared between the study arms, using Kaplan-Meier analysis and log-rank tests. Participants were considered to be lost if they were >6 weeks late for a scheduled follow-up visit, and they were censored before 12 months of follow-up if they had HIV-1 seroconversion, became pregnant, or remained in active follow-up at the completion of the trial in December 2006.

Because study medication was dispensed as DOT at clinic visits, adherence to therapy was closely related to attendance at follow-up visits, and participants were considered to be nonadherent when they were >2 weeks late for a scheduled visit. We compared the median adherence in each study arm by means of the Wilcoxon rank sum test and compared the proportion of visits at which the study drugs were not given by use of generalized estimating equations with binomial link and exchangeable correlation structure. The protocol required that study metronidazole/metronidazole placebo be withheld when open-label metronidazole treatment was provided.

Rates of primary and secondary end points and of reported adverse events in the 2 study arms were compared by means of Andersen-Gill proportional hazards models with robust variance estimates to allow for multiple events per woman. The incidence of HIV-1 seroconversion in the 2 study arms was compared by use of a Cox proportional hazards model. All analyses were conducted in accordance with the intention to treat principle. This study is registered with ClinicalTrials.gov (trial NCT00170430; available at: http://clinicaltrials.gov).

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Results

Between May 2003 and November 2005, a total of 378 women were screened for study eligibility, and 310 were enrolled; 155 were assigned to the active treatment arm and 155 to the placebo arm (figure 1). Of these, 151 women (97.4%) in the treatment arm and 152 (98.1%) in the placebo arm returned for at least 1 follow-up visit and were included in primary analyses (P > .99). The median number of follow-up visits did not differ significantly between the treatment arm (12 visits [interquartile range {IQR}, 8–12 visits]) and the placebo arm (12 visits [IQR, 9–12 visits]; P = .8). Kaplan-Meier analysis revealed that follow-up was 87% in the treatment arm and 92% in the placebo arm at 6 months and 79% in the treatment arm and 85% in the placebo arm at 12 months and that it did not differ significantly between the 2 arms (P = .2). The follow-up period concluded in December 2006.

Figure 1.
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Figure 1.

Participant flow through the study. Remained in active follow-up when the study closed in December 2006. IQR, interquartile range.

Participants in the 2 study arms did not differ significantly with respect to demographic, obstetrical, and behavioral characteristics and laboratory findings (table 1). The median age was 32 years (IQR, 27–38 years), and most participants had no secondary education. Women reported having had a median of 1 sex partner and having engaged in a median of 1 sex act in the past week, and more than half reported 100% condom use. Although the study protocol required that women did not have abnormal vaginal discharge or vulvovaginal pruritus at enrollment, laboratory findings revealed that >40% had vaginal infections. Mixed vaginal infections were present in 6 women (2%; 3 had BV and vaginal candidiasis, and 3 had BV and T. vaginalis infection). Depletion of vaginal Lactobacillus organisms was common, consistent with prior studies in this population [3, 5].

Table 1.
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Table 1.

Baseline characteristics of study participants.

Table 2.
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Table 2.

Incidence and cumulative number of vaginal infections and vaginal Lactobacillus colonizations, by study arm.

Table 3.
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Table 3.

Incidence and cumulative number of adverse events, by study arm.

Compared with the 56 women (18%) who were lost before completing 12 follow-up visits, those who completed the study had a slightly higher median age (32.2 years [IQR, 27.2–38.2 years] vs. 30.1 years [IQR, 26.1–34.8 years]; P = .04) and reported a longer median duration of sex work (4.5 years [IQR, 1.8–9.1 years] vs. 2.3 years [IQR, 0.7–6.3 years]; P = .008), a greater median number of pregnancies (2 pregnancies [IQR, 1–3 pregnancies] vs. 1 pregnancy [IQR, 1–2 pregnancies]), and a lower prevalence of vaginal washing (87% [221 of 254 women] vs. 98% [55 of 56]; P = .02).Womenwho remained in the study were more likely than women who were lost to follow-up to have vaginal candidiasis at the baseline visit (32 [13%] of 254 vs. 1 [2%] of 56; P = .02). There were no other significant differences between the women retained and those lost to follow-up.

Because medication was dispensed as DOT at monthly clinic visits, women were classified as nonadherent if they were >2 weeks late for a follow-up visit. On the basis of this definition, median adherence to the study regimen was 92% (IQR, 83%–100%) in the treatment arm and 92% (IQR, 83%–100%) in the placebo arm (P = .8). Study metronidazole/metronidazole placebo was not given at 51 (3.3%) of 1565 visits in the treatment arm and 44 (2.7%) of 1614 visits in the placebo arm (P = .5). Study fluconazole/fluconazole placebo was not given at 7 (0.4%) of 1565 visits in the treatment arm and 19 (1.2%) of 1614 visits in the placebo arm (P = .03).

Primary end points in the intervention and placebo arms of the trial are compared in table 2. Monthly treatment with metronidazole plus fluconazole reduced the number of episodes of BV by nearly half and produced similar increases in the frequency of colonization with Lactobacillus organisms, including those that produce H2O2. There were fewer episodes of vaginal candidiasis and trichomoniasis among recipients of active treatment, compared with women receiving placebo, but these differences were not statistically significant.

Although the primary BV end point was based on microscopy findings [11], we also evaluated the effect of the intervention on the incidence of clinically defined BV [12]. At the enrollment visit, 24 women (16%) in the treatment arm and 20 (13%) in the placebo arm had clinically defined BV (P = .5). During the follow-up period, BV was identified on the basis of clinical criteria at 150 visits in the treatment arm (incidence, 99 episodes per 100 person-years), compared with 300 visits in the placebo arm (incidence, 196.6 episodes per 100 person-years) (HR, 0.51; 95% confidence interval [CI], 0.42–0.62; P = .001).

Five women in the treatment arm and 7 in the placebo arm seroconverted to HIV-1 (HR, 0.6; 95% CI, 0.2–2.3; P = .6). Six women in each study arm acquired gonorrhea (HR, 1.0; 95% CI, 0.6 –1.7; P > .99).No severe adverse events, defined on the basis of criteria from the Division of AIDS, National Institute of Allergy and Infectious Diseases, occurred in either study arm. Nausea was reported at 36 visits in the treatment arm (incidence, 23.7 episodes per 100 person-years), compared with 21 visits in the placebo arm (incidence, 13.7 episodes per 100 person-years) (HR, 1.7; 95% CI, 1.0–2.9; P = .05) (table 3). There were no other significant differences in adverse events.

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Discussion

In this randomized trial of an intervention strategy for improving vaginal health in women at risk for HIV-1 acquisition, monthly DOT with metronidazole plus fluconazole significantly decreased the number of new episodes of BV and increased the frequency of vaginal colonization with Lactobacillus species. There were decreases in the incidences of vaginal candidiasis and T. vaginalis infection in the treatment arm, although they were not statistically significantly different from those in the placebo arm. These data addressed vaginal health in the broad context of both normal flora and the 3 major infectious causes of vaginitis, and they were intended to provide insight into a novel therapeutic approach to reduce the risk of HIV-1 acquisition in women. This study was not specifically directed at modifying clinical symptoms.

The results of our trial add to the limited data available on regimens for reducing the frequency of BV. A recent study of US women showed that, following successful treatment of symptomatic BV, suppressive therapy with 0.75% metronidazole gel on 2 nonconsecutive nights each week reduced clinically defined recurrence (relative risk [RR], 0.43; 95% CI, 0.25–0.73) and microscopy-defined recurrence (RR, 0.66; 95% CI, 0.39–1.12) [7]. Less frequent administration (on 5 consecutive nights every 3 months) of metronidazole 0.75% gel for prevention of BV was evaluated in Malawi [15]. Among HIV-1-seronegative women, this regimen resulted in a modest reduction in BV defined on the basis of Gram stain criteria, compared with placebo-buffered gel (adjusted RR, 0.90; 95% CI, 0.83–0.97). Overall, these data reinforce the persistent nature of BV, confirm that intermittent administration of suppressive therapy increases the likelihood of sustained cure, and suggest that higher doses and more frequent administration of metronidazole may be more effective than other metronidazole regimens against BV.

Similar to BV, vulvovaginal candidiasis frequently recurs [16]. A clinical trial published in 2004 demonstrated that, in women with a prior history of vaginal candidiasis, weekly treatment with 150 mg of oral fluconazole was effective at reducing recurrences [6]. The median time to clinical recurrence of candidiasis was 10.2 months in the fluconazole arm versus 4.0 months in the placebo arm (P < .001). In the trial presented here, monthly administration of 150 mg of fluconazole led to only a small reduction in the number of episodes of vaginal candidiasis identified by microscopy. Studies of women with recurrent vulvovaginal candidiasis have shown that weekly administration is more effective than monthly administration of fluconazole for reducing recurrences [6]. Considered together with our present findings, the data suggest that monthly dosing may have been insufficient to substantially reduce vaginal recolonization with Candida organisms in this population of female sex workers. The effect of fluconazole therapy may also have been counterbalanced by an increased risk of vaginal candidiasis following treatment of BV with metronidazole [7, 17, 18]. Because yeast cultures were not performed, it was not possible to evaluate rates of antifungal resistance and recolonization with non-albicans species of Candida in this study.

T. vaginalis is sexually transmitted, and efforts to reduce recurrences of infection have generally focused on treatment of sexual partners and promotion of safer sex [19]. In a community-based randomized trial of periodic mass treatment of STIs, metronidazole, azithromycin, and ciprofloxacin were provided every 10 months [20]. This strategy significantly reduced the incidence of trichomoniasis in intervention communities, compared with control communities (adjusted RR, 0.52; 95% CI, 0.35–0.79). In the present trial, monthly metronidazole therapy reduced the incidence of T. vaginalis infection to a similar extent, but the number of infections was fewer than expected on the basis of prior data from the parent cohort [21], and the difference between study arms was not statistically significant. The low incidence may reflect a lower risk among women who met trial inclusion criteria and the fact that all participants received monthly risk reduction counseling, free condoms, and directed treatment for T. vaginalis infection.

Studies that evaluated the efficacy of metronidazole for treatment of symptomatic BV have demonstrated resolution in 47%–90% of women at ≥4 weeks [22–27], with 7-day regimens generally producing higher rates of resolution, compared with single-dose treatment. For T. vaginalis infection, a single 2-g dose of metronidazole is the treatment of choice and has provided cure rates of 82%–88% [28–31]. Follow-up examinations conducted ≥1 month after treatment with a single 150-mg dose of oral fluconazole for vulvovaginal candidiasis revealed cure rates of 56%≥70% [32≥34]. Few trials for treatment of vaginal infections have been conducted in African women or in sex workers, so the cure rates for these populations are not well-defined.

Unblinding because of adverse effects has been suggested as a potential limitation in randomized trials of oral metronidazole therapy [15]. In this study, we observed only a modest increase in nausea, with no other significant differences in adverse events between the active treatment and placebo groups. Moreover, laboratory technicians evaluating the end points were blinded with respect to participants' clinical data. Thus, unblinding is unlikely to have influenced the results.

Overall, data from 98% of participants were included in analyses of the primary end points, and the average number of visits in both study arms substantially exceeded the predefined criteria for successful follow-up. The proportion of women included in the primary analyses and the overall retention rate compared favorably to those in recent HIV-1-prevention trials involving female sex workers [35, 36]. The sample size for this study provided excellent power for examining differences in the rates of BV, vaginal candidiasis, and Lactobacillus colonization (including colonization with H2O2-producing strains) between the 2 study arms. The final sample size provided less power for identifying differences in the incidence of T. vaginalis infection.

We used microscopic scoring criteria for the diagnosis of BV in our primary analyses [11]. Additional analyses demonstrated that the intervention produced similar reductions in episodes of clinically defined BV [12]. There are 2 reasons why microscopydefined criteria were selected for defining the primary BV end point. First, nearly 90% of these women reported vaginal washing, raising concern about whether the clinical criteria would produce reliable results in this population. Second, the presence of BV by Gram stain criteria has been associated with increased risk for HIV-1 acquisition in this population [3] and in a general population cohort of South African women [37]. Thus, resolution of BV by Gram stain criteria is a potentially important outcome for these women.

It is likely that these findings are generalizable to other populations of African women at risk for HIV-1 acquisition. Nonetheless, it should be noted that the efficacy of this regimen could vary in relation to population characteristics, including age, condom use, intravaginal practices, and prevalence of vaginal colonization with Lactobacillus organisms.

Vaginal infections are common and have been associated with increased risk for HIV-1 [2]. Given the high prevalence of these infections, interventions to reduce their frequency could have a major impact on the incidence of HIV-1 infection among African women. This trial demonstrated that periodic presumptive treatment with oral metronidazole and fluconazole reduced BV incidence and increased vaginal colonization with Lactobacillus organisms. Approaches that have a greater impact on vaginal infections are needed to maximize the potential usefulness of vaginal health interventions for reducing the risk of HIV-1 acquisition.

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Acknowledgments

Wethank our clinic staff, laboratory staff, and administrators, for valuable contributions to this study; the Mombasa Municipal Council, for allowing us to use their clinical facilities; Coast Provincial General Hospital, for providing laboratory space; our data safety and monitoring board, including James Hughes, Jeanne Marrazzo, and Peter Cherutich, for their careful review of the interim data; Joan Kreiss, for her important contributions to the development of the concept for this trial; Harborview Medical Center Investigational Drug Services Pharmacy, for providing valuable assistance with study product preparation and logistics; and the women who participated in the study, without whose time and effort this trial would not have been possible.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: National Institutes of Health (grant K23-AI52480) and Fogarty International Center (grant D43-TW00007 to W.M.H.).

  • Received October 3, 2007.
  • Accepted November 27, 2007.
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  1. J Infect Dis. (2008) 197 (10): 1361-1368. doi: 10.1086/587490
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